Orally effective methylphenidate extended release powder and aqueous suspension product

ABSTRACT

An oral methylphenidate powder which is reconstitutable into a final oral aqueous sustained release formulation containing at least about 50%, or at least about 80% by weight water based on the total weight of the suspension, is provided. The powder is a blend containing a combination of an uncoated methylphenidate-ion exchange resin complex, a barrier coated methylphenidate-ion exchange resin complex-matrix, and a water soluble buffering agent such that upon formed into an aqueous liquid formulation, the formulation has a pH in the range of about 3.5 to about 5, or about 4 to about 4.5. Following administration of a single dose of the oral aqueous methylphenidate suspension, a therapeutically effective amount of methylphenidate is reached in less than one hour and the composition provides a twelve-hour extended release profile.

BACKGROUND OF THE INVENTION

Methylphenidate hydrochloride (HCl) and dexmethylphenidate hydrochlorideboth have the empirical formula C₁₄H₁₉NO₂.HCl. Methylphenidate HCl is aracemic mixture of d,l-threo-methyl α-phenyl-2-piperidineacetatehydrochloride. Several commercial products, including, e.g., Ritalin®,Daytrana™, and Metadate™ contain methylphenidate HCl as the active drug.Dexmethylphenidate is the d-threo-enantiomer of racemic methylphenidatehydrochloride [Focalin® product literature]. There are severalcommercial products which contain dexmethylphenidate as the active drug.

The use of the central nervous system stimulants methylphenidate anddexmethylphenidate for the treatment of such conditions as attentiondeficit disorder (ADD) and attention deficit hyperactivity disorder(ADHD) in adults and children has been described [see, Focalin®,Concerta®, Ritalin®, Daytrana™ and Metadate® product literature]. Thisdrug may also be used to treat depression and cognitive impairmentfollowing Traumatic Brain Injury [See, product literature formethylphenidate hydrochloride tablet which is commercially availablefrom Lake Erie Medical DBA Quality Care Products LLC, and productliterature of the other drug products identified herein].

Solid dose extended release methylphenidate or dexmethylphenidateproducts are commercially available. These products include, e.g.,Focalin® XR, Concerta®, Ritalin® LA, and Metadate®. However, toapplicant's knowledge, there is no commercially available extendedrelease liquid product containing a methylphenidate.

The methylphenidate based medications are predominantly prescribed forchildren, including children as young as 3 years old where they havedifficulty swallowing the solid dosage forms. There remains a need for astable, long-acting liquid methylphenidate product which can beconveniently delivered in an oral, titratable formulation.

SUMMARY OF THE INVENTION

The present invention provides a methylphenidate extended release powderwhich may be mixed with water to form an orally administrable extendedrelease aqueous suspension. Also provided is the orally administrablemethylphenidate extended release aqueous suspension which is stable atroom temperature. Methods of treating patients in need thereof withthese methylphenidate extended release suspensions are further providedby the invention.

As used herein “methylphenidate” includes the active ingredient which iseither (i) racemic mixture of two optical isomersd-threo-methylphenidate and l-threo-methylphenidate or (ii) the activeisomer d-threo-methylphenidate (also known as dexmethylphenidate). Forconvenience, methylphenidate is abbreviated “MPH” herein. When referenceis made herein to methylphenidate or MPH, it will be understood thateither the racemic mixture (typically 50/50 d- to l-) ordexmethylphenidate is encompassed by this term. Where only the racemateor dexmethylphenidate is desired, reference will be specifically made toone or the other. Thus, for the formulations described herein, themethylphenidate may be independently selected from racemicmethylphenidate (e.g., a 50/50 mixture of D-methylphenidate andL-methylphenidate), and dexmethylphenidate.

In one aspect, the invention provides a methylphenidate aqueous extendedrelease suspension comprising at least 50% by weight water based on thetotal weight of the liquid component of the suspension, wherein extendedrelease is as defined herein. In one embodiment, the suspension containsat least about 80% water by weight based on the total weight of thesuspension. In one embodiment, the suspension has a pH of about 3.5 toabout 5. In another embodiment, the suspension has a pH of about 4 toabout 5, or about 4 to about 4.5, or about 4.2.

In one embodiment, a methylphenidate aqueous extended release oralsuspension is characterized by providing a methylphenidate plasmaprofile of any of FIG. 1, 3 or 4 at a dose equivalent to 72 mg and 60 mgof racemic methylphenidate HCl, respectively. In one embodiment, themethylphenidate aqueous extended release oral suspension comprises animmediate release methylphenidate component and a sustained releasemethylphenidate component.

In another aspect, the invention provides a methylphenidate extendedrelease powder blend formulation which is reconstitutable into an orallyadministered aqueous extended release suspension formulation. Theextended release powder blend formulation comprises (i) an immediaterelease methylphenidate component, (ii) a sustained release barriercoated methylphenidate-ion exchange resin complex-matrix, and (iii) anoptional water soluble buffering agent. Upon being prepared as (e.g.,reconstituted) an orally administrable aqueous extended releasesuspension formulation, the suspension has a pH in the range from about3.5 to about 5, or about 4 to about 5, or about 4 to about 4.5. In oneembodiment, the immediate release methylphenidate component is anuncoated methylphenidate-ion exchange resin complex, optionally incombination with a matrix forming polymer. In another embodiment, thebarrier coating is a cured water-permeable, high tensile strength, waterinsoluble, barrier coating comprising a polyvinylacetate polymer and aplasticizer.

Alternatively, the barrier coating is selected from an ethylcellulosebarrier coating and/or a coating based on poly(ethylacrylate-co-methylmethacrylate-cotrimethyl-ammonium-ethylmethacrylate chloride) polymer.

In a further embodiment, the invention provides an aqueousmethylphenidate extended release suspension formulation having a pH inthe range of about 3.5 to 5 and comprising methylphenidate extendedrelease powder blend as described herein, the water-soluble bufferingagent to provide the desired pH, and water. In one embodiment, at leastabout 80% of the liquid component of the suspension is water.

In one embodiment, the invention provides an oral aqueousmethylphenidate extended release suspension formulation reconstitutedfrom a methylphenidate extended release powder blend in a liquidsuspension base comprising at least about 80% water. The methylphenidateextended release powder blend comprises a combination of (a) a sustainedrelease, cured, barrier coated methylphenidate-ion exchange resincomplex-matrix, wherein the barrier coating comprises polyvinylacetateand a plasticizer and (b) an immediate release uncoatedmethylphenidate-ion exchange resin matrix, wherein the complex of (a)and the matrix of (b) are granules having an average size range of about100 microns to about 250 microns. Optionally, the extended releasepowder blend further comprises an optional diluent granule comprising abuffering agent such that upon being formed into an aqueous liquidsuspension, the suspension has a pH in the range of about 4 to about4.5.

In a further embodiment, the invention provides a method of treatingpatients with a disorder for which methylphenidate is regulatoryapproved by administering an oral aqueous methylphenidate extendedrelease suspension formulation as described herein.

Still other aspects and advantages of the invention will be apparentfrom the following detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a linear plot of mean methylphenidate plasma concentrationversus time. This study provides the pharmacokinetic (pK) profile of anoral aqueous extended release formulation of the invention containingthe methylphenidate ER powder blend of Example 1 suspended in water toform an aqueous methylphenidate liquid suspension formulation having aconcentration of 25 mg per 5 mL which formulation provides both animmediate release and an extended release profile. The oral aqueousliquid extended release formulation was dosed to provide an amount ofmethylphenidate equivalent to a 72 mg dose of methylphenidate HCl. Acommercially available extended release methylphenidate HCl tablet(Concerta® solid formulation) was used for comparison.

FIG. 2 illustrates the pH-Chemical Stability of ReconstitutedMethylphenidate-Ion Exchange Resin Powder for Oral Suspension, 25 mg/5mL, as described in Example 6.

FIG. 3 provides the pK profile of an oral aqueous extended releaseformulation of the invention containing the methylphenidate ER powderblend of Example 1 suspended in water to form an aqueous methylphenidateliquid suspension formulation having a concentration of 25 mg per 5 mL,which formulation provides both an immediate release and an extendedrelease profile. For this study (see Example 7A), the oral aqueousliquid extended release formulation was dosed to provide an amount ofmethylphenidate equivalent to a 60 mg dose of methylphenidate HCl.

FIG. 4 provides the results of an absorption study (Example 7B),illustrated by the mean d-methylphenidate plasma concentrations againsttime of an oral aqueous extended release formulation of the inventionequivalent to a 60-mg methylphenidate HCl dose under fed (A, n=27) andfasting (B, n=28) conditions.

FIG. 5 illustrates the results of the study of Example 8, showing thechange from baseline in the attention and behavior of the subjects in alaboratory classroom using the Swanson, Kotin, Agler, M-Flynn, andPelham (SKAMP) rating scale. This is charted as the SKAMP-CombinedScore.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect the invention provides a methylphenidate (MPH) extendedrelease powder blend. The MPH extended release powder blend contains, ata minimum, a combination of an immediate release MPH component and asustained release MPH component. While useful for formulation as asolid, the MPH extended release powder blend can readily be prepared asa suspension for oral delivery at the time the product needs to be used.

Suitably, following administration of a single dose of the oral MPHextended release suspension, in some embodiments, a therapeuticallyeffective amount of MPH is reached as soon as about forty-five minutesand the formulation provides an extended release profile to at leastabout 12 hours.

As is often the case with psychoactive drugs, a therapeutic result forMPH is not solely related to plasma levels of the drug. Thus, “atherapeutically effective amount” of MPH includes the minimum amount ofthe drug required to provide a clinically observable psychologicaland/or behavioral response.

As used herein, the term “extended release” refers to compositions whichare characterized by having at least one of the active components (i.e.,methylphenidate or dexmethylphenidate) having a release over a period ofat least about 12 hours. As with formulations described herein,“extended release” may be achieved by a single formulation containingboth an “immediate release” component (release in less than 1 hour,e.g., as soon as about 45 minutes or as soon as about 30 minutes) and a“sustained release” (i.e., release for about 12 hours). The releaseprofile may be assessed via in vitro dissolution using techniques knownto those of skill in the art [e.g., USP basket method, Paddle Method,channel flow method, or other methods known in the literature]. Therelease profile can be assessed in vivo (e.g., for bioavailabilitydeterminations), using plasma concentrations to assess maximum plasmaconcentration (C_(max)) and area under the curve (AUC). Such assays arewell known to those of skill in the art. [see, e.g., W. Wargin, et al.,Pharmacokinetics of methylphenidate in man, rat and monkey. J PharmacolExp Ther August 1983 226:382-386].

“C_(max)” is the maximum observed plasma concentration, calculated asthe mean of the individual maximum blood plasma concentrations.

The term “mean maximum plasma concentration” (mean C_(max)) is definedfor the purposes of the present invention as the maximum mean plasmadrug concentration.

“Mean plasma concentration” is the arithmetic mean blood plasmaconcentration.

The term “T_(max)” is the time at which the peak (maximum) observedblood plasma drug concentration for each individual participating in thebioavailability study.

The term “AUC_(0-∞)” or “AUC_(inf)” is the mean area under the plasmaconcentration-time curve extrapolated to infinity. It is calculated asthe arithmetic mean of the area under the plasma concentration-timecurve from time 0 extrapolated to infinity, calculated for eachindividual participating in the bioavailability study.

AUCpR is the area under the curve to the population median T_(max) ofthe reference formulation. AUC_(0-t) is the area under theplasma/serum/blood concentration-time curve from time zero to time t,where t is the last time point with measurable concentration forindividual formulation.

T/R ratio refers to the test formulation (methylphenidate polistirex 25mg/5 mL ER oral suspension) to reference (R) formulation.

Intra-subject CV % refers to the geometric (CV) coefficient of variationbetween subjects.

The term “half-life” is the apparent terminal elimination half-life(T_(1/2)).

The term “immediate release” is the release of an active ingredient(e.g., MPH) from a pharmaceutical formulation where the rate of releaseof the active pharmaceutical ingredient from the pharmaceuticalformulation is not retarded by means of a controlled release matrix orother such means and where the components of the pharmaceuticalformulation are designed such that, upon ingestion, maximum exposure ofsaid active pharmaceutical ingredient to body tissues occurs in theminimum period of time. As described herein, an “immediate release” MPHcomponent preferably releases in less than 1 hour, e.g., as soon asabout 45 minutes or as soon as about 30 minutes. Further, in oneembodiment, the MPH immediate release component releases at least about50% of the MPH within about the first hour following administration, andat least about 80% of the MPH within about 90 minutes followingadministration. As will be seen from the following detailed description,a MPH-ion exchange resin complex, optionally in a matrix, and mayprovide the immediate release component.

The term “initial administration” is defined for purposes of the presentinvention as the first single dose of a formulation containing an activeingredient administered to a patient or subject or the first doseadministered to a patient or subject after a suitable washout period.

As used herein, a therapeutically effective amount of MPH is at leastthe minimum amount of MPH which reduces or eliminates the symptomsassociated with a condition for which MPH has been approved for use.Appropriate doses are discussed in more detail later in thisspecification.

The invention minimizes stability problems attributed to prior artliquid MPH formulations and permits the orally administrable MPHextended release suspension formulation to be primarily aqueous based.The aqueous liquid suspension of the invention is one in which water isgreater than 50% by weight of the liquids in the suspension. In oneembodiment, water is greater than about 60%, greater than about 70%,greater than about 80%, greater than about 90%, or up to 100% by weightof the liquid component of the suspension formulation.

In contrast to prior art formulations which have been reported as amixture of primarily non-aqueous solvents in combination with water,requiring more than 50% non-aqueous solvents, the present invention isan aqueous liquid formulation. The formulations of the invention containless than 10% non-aqueous solvents, and in certain embodiments, lessthan 5%, or less than 2% non-aqueous solvents. In further embodiments,the formulations of the invention may optionally also contain minimalamounts of components which are humectants, e.g., less than about 10%.

Additionally, the liquid suspension MPH extended release product makesit convenient for physicians to titrate the dose for patients tointroduce the drug in incremental doses of medication or for patientswho require incremental doses of medication so as to better tolerate thedrug. This ability to titrate the dose allows physicians to take intoconsideration individual patient needs, including factors like age, bodyweight and individual response to the medication without the need fortaking multiple doses of an immediate release product over a 12 hourperiod.

In one embodiment, the invention provides a MPH extended release powderblend formulation which is reconstitutable into an orally administrableaqueous extended release suspension formulation. Suitably, the MPHextended release powder blend formulation contains, at a minimum, animmediate release methylphenidate component and a sustained releasebarrier coated methylphenidate-ion exchange resin complex-matrix,optionally further in combination with a water soluble buffering agent.Upon reconstitution of the MPH extended release powder blend into anaqueous suspension formulation by combining with water, the formulationis adjusted to a pH in the range from about 3.5 to about 5, or about 4to about 4.5, or about 4.2.

In one embodiment, the invention provides an MPH extended release powderblend which contains, at a minimum, both a barrier coated MPH-ionexchanged resin complex-matrix and an uncoated MPH-ion exchange resincomplex in combination. This powder blend is designed to bereconstituted for oral delivery as an aqueous suspension. Alternatively,the powder blend can be administered by sprinkling on food (e.g.,applesauce), or by other methods. The oral MPH ER powder blend describedin the above embodiment contains a dried granular uncoatedmethylphenidate-ion exchange resin complex and a dried granular barriercoated sustained release methylphenidate-ion exchange resincomplex-matrix.

In one embodiment, the powder blend further comprises water-solublediluent granules which contain at a minimum, a water soluble bufferingagent, wherein upon being formulated into an aqueous liquid suspension,the suspension formulation has a pH in the range of about 3.5 to 5,about 4 to about 4.5, or about 4.2. Optionally, excipients including,e.g., one or more of a surfactant, a sweetener, and/or a preservative,may be contained within the diluents granules and thus form a part ofthe MPH ER powder blend. Alternatively or additionally, these optionalexcipients may be included in the placebo suspension base. Thesurfactant may be a poloxamer. The buffering agent may be selected fromone or more of an acid selected from the group consisting of citricacid, ascorbic acid, acetic acid, tartartic acid, phosphoric acid, apharmaceutically acceptable salt of citric acid, ascorbic acid, aceticacid, tartartic acid, phosphoric acid, or a mixture of an acid and asalt. In one embodiment, the buffering agent is a mixture of sodiumcitrate and anhydrous citric acid.

A “methylphenidate-ion exchange resin complex” refers to the productresulting from loading a methylphenidate salt onto a cation exchangeresin. Methods for preparing such complexes have been described, e.g.,in WO 2007/109104, incorporated herein by reference. This describes thecomplexation which occurs when the active and the ion exchange resin aremixed together in an aqueous medium to facilitate the “exchange” betweenthe salt of the MPH and the “cation” of the ion exchange resin and theformation of the complex, which may be referred to as “methylphenidatepolistirex”.

WO 2007/109104 also describes polyvinylacetate-based barrier coatingswhich are particularly well suited for use in the formulations describedherein to provide a sustained release coat over the MPH-ion exchangeresin complex-matrix. However, one skilled in the art can select otherbarrier coatings to provide the sustained release characteristics toMPH-ion exchange resin complex-matrix.

As used herein, a “precoated” MPH-ion exchange resin complex or a“precoated” MPH-ion exchange resin complex-matrix refers to a particlewhich is to be subsequently coated with a barrier coating as definedherein. In some embodiments, where the MPH-ion exchange resin or MPH-ionexchange resin complex-matrix is to be used for the immediate releasecomponent and no barrier coating is to be applied, it is referred to as“uncoated”.

As used herein, a barrier coat is a water-permeable, water-insoluble,non-ionic polymer or co-polymer which confers modified release andparticularly, in the present invention, sustained release for the MPH.As described herein, the barrier coat is applied, e.g., as an aqueoussuspension, over the precoated MPH-ion exchange resin complex-matrix andforms a separate layer thereon. Preferably, the barrier coat is directlyover the precoated MPH-ion exchange resin complex-matrix and the barriercoat layer, i.e., there are no intervening layers between the barriercoat and the precoated MPH-ion exchange resin complex-matrix. Dependingupon the polymeric material selected, the barrier coat polymer orco-polymer may be cured. These polymers and their curing requirementsare discussed in more detail elsewhere in this specification.

A “methylphenidate-ion exchange resin complex-matrix” refers a MPH-ionexchange resin complex which is further combined, e.g., prior to orduring granulation, with a polymeric material which forms a matrix withthe MPH-ion exchange resin complex.

In one embodiment, a “methylphenidate polistirex” refers to the complex(salt) formed by loading methylphenidate onto an ion exchange resin.

The term “matrix forming polymer” or “matrix forming polymeric material”refers to both water-insoluble polymers/co-polymers and water-solublepolymers/co-polymers which form a matrix with the MPH-ion exchange resincomplex upon being admixed or granulated therewith. Suitably, the matrixforming polymer is non-reactive with the MPH. The matrix forming polymermay be a water-insoluble polymers/co-polymers and polymer systems whichalso function as release retardants as described herein, and thosehydrophilic polymer systems which have been described in the literatureas impregnating or solvating agents. In one embodiment, a MPH-ionexchange resin complex-matrix may include more than one matrix-formingpolymer system. For example, an MPH-ion exchange resin complex-matrixmay contain both a hydrophilic polymer and a hydrophobic polymer.

The words “comprise”, “comprises”, and “comprising” are to beinterpreted inclusively rather than exclusively. The works “consist”,“consisting”, and its variants, are to be interpreted exclusively,rather than inclusively.

As used herein the term “about” means a variability of 10% from thereference given, unless otherwise specified.

Methylphenidate/Dexmethylphenidate-Ion Exchange Resin Complex

The active drug component of the extended release powder blendformulation and the extended release aqueous suspension formulation hasbeen described herein as racemic methylphenidate or dexmethylphenidate.These active drugs may be purchased commercially, e.g., methylphenidateHCl and dexmethylphenidate HCl may be purchased. Alternatively, theseactive compounds may be prepared using methods known to those of skillin the art. Processes for the synthesis of methylphenidate and itsanalogs have been described. See, e.g., WO 2010/080787; U.S. Pat. Nos.2,507,631 and 2,957,880, as have processes for synthesis ofthreo-methylphenidate and its d-enantiomer have been reported. See,e.g., US Patent Application Publication No. 2006/0135777.

A selected MPH can be complexed with, or loaded onto, a cation exchangeresin, using methods which are known in the art. See, e.g., WO2007/109104, and the documents cited therein. Cationic exchange resinsare readily selected for use as described herein.

Cationic exchange resins vary in strength, i.e., in their ability toexchange cations. In one embodiment, a relatively strong cationic resin,e.g., Amberlite® IRP69, manufactured by Rohm and Haas (a sulfonatedcopolymer of styrene and divinylbenzene) is selected. Alternatively, onemay select a relatively weak cationic exchange resin, e.g., Amberlite®IRP88 [Rohm and Haas, a crosslinked polymer of methacrylic acid anddivinylbenzene)], a weakly acidic (potassium ion) cation exchange resinwith 4% cross-linked methacrylate (100 to 500 mesh, equiv to about 150microns to about 27 microns, ASTM standard) or Amberlite® 64 (amethacrylic acid and divinylbenzene polymer (hydrogen ion) polyacrilexresin, Rohm and Haas, with a particle size ranging from 100 to 400 mesh(equiv to 35 microns to 150 microns, ASTM standard size), capacity ˜10meq/g by dry weight). Further, either regularly or irregularly shapedparticles may be used as cation exchange resins according to the presentinvention. Regularly shaped particles are those particles thatsubstantially conform to geometric shapes such as spherical, elliptical,cylindrical and the like, which are exemplified by Dowex® 50WX8 (The DowChemical Company). Irregularly shaped particles are all particles notconsidered to be regularly shaped, such as particles with amorphousshapes and particles with increased surface areas due to surfacechannels or distortions. Irregularly shaped ion-exchange resins of thistype are exemplified by Amberlite® IRP-69 (manufactured by Rohm & Haas),the use of which is illustrated in the examples below. This cationexchange resin is a sulfonated polymer composed of polystyrenecross-linked with about 8% of divinylbenzene, with an ion-exchangecapacity of about 4.5 to 5.5 meq/g of dry resin (H⁺-form). Anothercation exchange resin having similar properties is Dowex® 50WX8 (H+form, linear formula, C₁₀H₁₂.C₁₀H₁₀.C₈H₈)_(x), 200-400 mesh particlesize, which is equivalent to about 75 microns to about 35 microns, ASTMstandard). Amberlite® IRP-69 consists of irregularly shaped particleswith a size range of about 100 to about 500 mesh (about 150 microns toabout 27 microns, ASTM standard). Dowex® 50WX8 is more regularly shaped.Resins are generally purchased with a size ranging from about 25 micronsto about 400 microns. However, other sizes may be selected, or largersized particles may be milled to provide smaller particle sizes.

The selected ion exchange resins may be further treated by themanufacturer or the purchaser to maximize the safety for pharmaceuticaluse or for improved performance of the compositions. Impurities presentin the resins may be removed or neutralized by the use of commonchelating agents, anti-oxidants, preservatives such as disodium edetate,sodium bisulfite, and so on by incorporating them at any stage ofpreparation either before complexation or during complexation orthereafter. These impurities along with their chelating agent to whichthey have bound may be removed before further treatment of the ionexchange resin.

The amount of methylphenidate that can be complexed with a resin willtypically range from about 5% to about 50% by weight of the MPH-ionexchange resin complex particles. A skilled artisan with limitedexperimentation can determine the optimum loading for any MPH-ionexchange resin complex. In one embodiment, loading of about 10% to about40% by weight, more desirably, about 15% to about 30% by weight, orabout 25% of the MPH-ion exchange resin complex particles can beemployed. In one embodiment, a composition of the invention contains MPHcomplexed to a sodium polystyrene sulfonate resin in at a ratio of 20 wtMPH (based on the weight of the MPH salt) to 300 wt resin to 80 wt MPH(based on the weight of the salt) to 100 wt resin. In anotherembodiment, the MPH (based on the weight of the salt) to resin ratio is4:10 to 1:10, or about 4:10 to about 2:10. In a further embodiment, thedexMPH permits the use of about half the amount of active required whenracemic MPH is the active drug.

In one embodiment, following complexation, a MPH-ion exchange resincomplex may be, in no particular order, milled to achieve a desired sizerange and dried (e.g., to a moisture content below about 10%, e.g.,about 3% to about 7%), and then stored for future use. In oneembodiment, the complex is milled or passed through a sieve to provide aparticle size ranging from about 40 microns to about 410 microns toenhance mouth feel (i.e., texture), or about 50 microns to about 250microns. These particles may be either regularly or irregularly shaped.In some embodiments, the average particle size of the uncoated MPH-ionexchange resin complex or the average particle size of the coated MPHion exchange resin complex is milled to a size of about 100 to about 200microns. These particle sizes may be determined using sieve analysisthrough a sieve shaker having USP standard wire mesh sieves conformingto ASTM specifications.

In one embodiment, a matrix forming polymer is combined with the MPH-ionexchange resin complex following only partial complexation, or byreducing the moisture content of the wet MPH-ion exchange resin complexto a range of between about 15 to about 25%, or another suitable amount.Treatment of the MPH-ion exchange resin complex with the matrix formingpolymer is as follows.

MPH-Ion Exchange Resin Complex-Matrix

Optionally, a matrix-forming polymer is used to assist in processing anuncoated or precoated MPH-ion exchange resin complex. For example, amatrix-forming polymer may be used to facilitate granulation of theimmediate release MPH component (e.g., an uncoated MPH-ion exchangeresin complex). Alternatively, the matrix-forming polymer may be usedfor another purpose.

In one embodiment, a polyvinylpyrrolidone polymer [e.g., such as may bepurchased commercially as Kollidon® 30] is combined with themethylphenidate-ion exchange resin complex in order to facilitategranulation prior to coating. Other hydrophilic polymeric granulatingagents may include water-soluble polymeric materials which have beendescribed in the art as impregnating agents or solvating agents andwhich function in the present application as granulating agents. In oneembodiment, the granulating agent is a polyethylene glycol. Examples ofdesirable impregnating/solvating agents include those described in U.S.patent application Ser. No. 11/724,966, filed Mar. 15, 2007, Publishedas US 2007-0215511A, Sep. 20, 2007, and Meadows, US 2003-0099711, whichare incorporated herein by reference, or in U.S. Pat. No. 4,221,778 andpublished US Patent Application Publication No. 2003/009971 A1, thedisclosures of which are incorporated herein by reference. Specificexamples of other impregnating agents include propylene glycol,polyethylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose,hydroxypropyl cellulose, and sorbitol.

Optionally, the MPH release rate from the compositions of the presentinvention may be further prolonged or modified by treating the MPH-ionexchange resin complex prior to the application of the water-permeablediffusion barrier coating described herein, with a release retardantwhich is a water-insoluble polymer or a combination of a water-insolublepolymers.

The release retardant does not form a separate layer on the MPH-ionexchange resin complex, but forms a matrix therewith. Examples ofsuitable release retardants include, for example, a polyvinyl acetatepolymer or a mixture of polymers containing same (e.g., KOLLICOAT® SR30D), cellulose acetates, ethylcellulose polymers (e.g., AQUACOAT™ECD-30 or SURELEASE™), acrylic based polymers or copolymers (e.g.,represented by the EUDRAGIT family of acrylic resins), cellulosephthalate, or any combination of such water-insoluble polymers orpolymer systems, all herein defined as “release retardants”. Theseretardants when used may further prolong or alter the release of the MPHfrom the ion exchange resin complex/matrix and maximize attaining thedesired release profile. Further, use of release retardant permits insome cases lowering the amount of coating thickness needed to attain aprolonged MPH release of up to about 12 hours. These retardants can beused in either substantially pure form or as a commercial preparationobtained from a vendor. The preferred release retardant is a polyvinylacetate polymer as described herein or an acrylic polymer from theEUDRAGIT family. Examples of suitable acrylic polymers from the EUDRAGITfamily may include, e.g., a copolymer comprising ethyl acrylate andmethyl methacrylate (e.g., EUDRAGIT NE-30D), or EUDRAGIT RS, RL30D,RL100, or NE, which are largely pH-independent polymers; although lessdesirable, certain pH-dependent members polymers including, e.g.,members of the EUDRAGIT polymer family, e.g., the L, S, and E, polymersmay be selected.

The quantity of polymer that is added to an uncoated or precoatedMPH-ion exchange resin complex as a matrix forming polymer typicallyranges from about 1% to about 30%, or about 3 to about 20%, or about 3to about 10%, about 10% to about 15%, about 15 to 25%, or about 1 toabout 5% or more by weight of the uncoated or precoated MPH-ion exchangeresin particulates prior to their being coated. However, higher or loweramounts may be selected. In one embodiment, where it is desired for thematrix forming polymer to have little or no affect on release rate, ahydrophilic polymer may be selected and used in a higher amount, whereasa hydrophobic release retardant if selected for use will be used at alower amount. Following admixing, the uncoated or precoated MPH-ionexchange resin complex particles with the matrix forming polymer, themixture is dried and the MPH-ion exchange resin complex-matrix granulesare milled appropriately to the desired particulate size.

For the precoated MPH-ion exchange resin complex-matrix which will becoated and the uncoated MPH-ion exchange resin complex, the particlesare milled though a size below about 410 microns, or generally in therange of about 50 microns to about 410 microns, or about 100 microns toabout 410 microns. This can be achieved, e.g., using a CO-MIL devicefitted with a 40 mesh screen. In one embodiment, the particles have anaverage size of about 100 to about 250 microns, or about 100 to about200 microns. In some cases, the milling may be carried out before thecomplete drying of the complex or complex matrix and then again furtherdrying followed by milling to obtain the desired complexcharacteristics. These particle sizes may be determined using sieveanalysis through a sieve shaker having USP standard wire mesh sievesconforming to ASTM specifications.

Barrier Coat for Sustained Release

The sustained release component of a MPH extended release powder blendof the invention contains a methylphenidate-ion exchange resincomplex-matrix with a barrier coating which modifies the release profileof the methylphenidate-ion exchange resin complex-matrix such that themethylphenidate has about a 12 hour sustained release profile. In oneembodiment, the barrier coating layer is about 10% to about 70%, byweight, or about 15% to about 65%, by weight, of the precoatedmethylphenidate-ion exchange resin complex-matrix in order to providethe sustained release component. In another embodiment, the barriercoating layer is about 20% to about 50%, about 25% to about 40% byweight, about 25% to about 35% by weight, or about 30%, by weight of theprecoated methylphenidate-ion exchange resin complex-matrix (i.e., priorto coating).

In one embodiment, the barrier coating is applied as an aqueousdispersion which is dried and cured in order to provide the desiredsustained release profile (e.g., polyvinylacetate orethylcellulose-based coatings). Such a cured barrier coating layer maybe in the range of about 15% by weight to about 70% by weight, or about20% by weight to about 60% by weight, or about 30% by weight to about45% by weight, based on the total weight of the precoatedmethylphenidate-ion exchange resin complex-matrix. In anotherembodiment, the barrier coating is a solvent-based coating system orother polymeric system which does not require curing in order to providethe desired sustained release profile. Such a barrier coating layer(e.g., a Eudragit or Eudragit blend as described herein) may be in therange of about 10% by weight to about 50% by weight, or about 15% byweight to about 45% by weight, or about 25% by weight to about 35% byweight of the precoated methylphenidate-ion exchange resincomplex-matrix. Still other suitable ranges can be determined by one ofskill in the art, having been provided with the information herein.

In one embodiment, the barrier coating is applied over the MPH-ionexchange complex-matrix as an aqueous dispersion, dried, and milled orpassed through a screen such that the barrier coated MPH-ion exchangecomplex-matrix particles are in the same size range as described in thepreceding paragraph, i.e., in the range of about 50 to about 410microns.

In one embodiment, the aqueous dispersion is a water insoluble polymercomprising a polyvinyl acetate polymer, or a blend of polymerscomprising a polyvinyl acetate polymer. In one embodiment, the barriercoating further contains a plasticizer, which can facilitate uniformcoating of the MPH-ion exchange resin complex and enhances the tensilestrength of the barrier coating layer.

One coating composition useful in the present invention is applied inthe form of an aqueous dispersion containing polyvinyl acetate (PVA)polymer based aqueous coating dispersion and a plasticizer. The PVA isinsoluble in water at room temperature. The PVA may be used in eithersubstantially pure form or as a blend. Where the barrier coatingcomprises a PVA polymer, the PVA polymer is present in an amount ofabout 70% to about 90% w/w of the final barrier coating layer, at leastabout 75%, at least about 80%, about 85% w/w of the final barriercoating layer. Generally, a plasticizer is used in the percent range, ora mixture of plasticizers combine to total about 2 to about 50% byweight of the coating layer, more preferably about 2.5% to about 20% byweight of the coating layer on the coated MPH-ion exchange resincomplex. Preferably a plasticizer is in a range of about 2.5 to about15% by weight of the coating layer based on the coated complex providesthe most desirable properties. Suitable plasticizers may be watersoluble and water insoluble. Examples of suitable plasticizers include,e.g., dibutyl sebacate, propylene glycol, polyethylene glycol, polyvinylalcohol, triethyl citrate, acetyl triethyl citrate, acetyl tributylcitrate, tributyl citrate, triacetin, and Soluphor® P (2-pyrrolidone),and mixtures thereof. Other plasticizers are described in patentapplication publication US 2003/0099711 A1, May 29, 2003, page 4 (0041)the disclosure of which is incorporated herein by reference.

A commercial polyvinylacetate blend contains primarily a polyvinylacetate polymer, a stabilizer, and minor amounts of a surfactant such assodium lauryl sulfate. Where the barrier coating comprises PVP as thestabilizer component, the final barrier coating layer generally containsabout 5 to about 10% w/w of polyvinyl pyrrolidone. In one desiredembodiment, the aqueous based barrier coating solution is KOLLICOAT® SR30 D (BASF Corporation) and whose composition is about 27% PVA polymer,about 2.7% polyvinylpyrrolidone (PVP), about 0.3% sodium lauryl sulfate(solids content 30% w/w), mixed with a plasticizer. See, also, U.S. Pat.No. 6,066,334 and U.S. Pat. No. 6,026,277, which is incorporated byreference herein. The PVP and surfactant help stabilize the aqueousdispersion of the PVA. Generally, such stabilizing components arepresent in an amount totaling less than about 10% w/w, and preferablyless than about 5% w/w. Optionally, a selected surfactant is present inan amount of about 1% or less. In one embodiment, the surfactant is anon-ionic surfactant. Optionally, an ionic surfactant may be selected.

In a particularly desirable embodiment, the desired modified release isobtained when the coating layer formed by application of the aqueousdispersion containing the KOLLICOAT® SR-30D-plasticizer is dried andcured. Preferably, the coating is cured for about 1 to about 24 hours.In alternate embodiments, the coating is cured for about 4 to about 16hours, and preferably about 5 hours at high temperature, e.g., about 50°C. to about 65° C., and preferably about 60° C. Thus, in one embodiment,the methylphenidate-cation exchange resin complex, matrix has a curedwater-permeable, high tensile strength, water insoluble, barrier coatingcomprising a non-ionic polymer and a plasticizer and having anelongation factor in the range of about 150% to 400%. In one embodiment,the barrier coating comprises a polyvinyl acetate polymer, a stabilizer,a surfactant and a plasticizer. In one embodiment, a barrier coatingcomprises about 2.5 to about 15% of plasticizer, about 70 to about 90%polyvinylacetate, about 5 to about 10% polyvinylpyrrolidone, and about0.1 to about 1% surfactant.

Optionally, another barrier coating may be selected. See, e.g., thebarrier coatings described in Kolter et al, U.S. Pat. No. 6,066,334 andU.S. Pat. No. 6,046,277 and Mehta et al, US Published Patent ApplicationNo. US 2007-0215511A, published Sep. 20, 2007, and its counterpartapplication, WO 2007/109104, which are incorporated herein by reference.See, also, e.g., Wen, U.S. Pat. Nos. 6,046,277 and 6,001,392; Meadows,US Published Patent Application No. 2003/009971 and related applicationWO 03/020242; Sovereign Pharmaceuticals, WO 2006/022996 and relatedapplications US Published Patent Application Nos. US2005/232986;US2005/232987; US2005/232993; US2005/266032.

Alternatively, other known aqueous or non-aqueous barrier coatings havebeen described in the literature and/or which are commercially availablecould be used for the coating process, but are less desirable for thereasons described in US Patent Publication No. US 2007-0215511A and inthe literature cited in the background therein. See, e.g., Bess, et al,U.S. Pat. No. 7,067,116; Goede et al, U.S. Pat. No. 6,667,058, Wen etal, U.S. Pat. No. 6,001,392, among others. Such coating materialsinclude ethylcellulose based extended release coatings, e.g., Aquacoat™ethylcellulose polymer extended release coating and Surelease®.Surelease® is available from Colorcon as an aqueous ethyl cellulosedispersion containing water (70.6% w/w), ethylcellulose (18.8% w/w),ammonium hydroxide (4.4% w/w), a medium chain triglyceride (4.0% w/w),and oleic acid (2.2% w/w).

In one embodiment, the coating may be a EUDRAGIT™ brand acrylate basedcoating materials [including, e.g., a poly (ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) polymersystem]. For example, Eudragit™ RS 30D [a pH-independent, 30% aqueousdispersion of poly (ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1],or Eudragit™ RL 30D [a 30% aqueous dispersion, pH independent polymer,poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethylmethacrylate chloride) 1:2:0.2] may be selected as the barrier coating.In one embodiment, a blend of Eudragit™ RS 30D and Eudragit™ RL 30D maybe prepared to optimize the hydrophilicity/hydrophobicity of the film inorder to achieve desirable release profiles. Optionally, talc may bemixed with one of the Eudragit™ products to improve flow during coatingand to address issues of tackiness of the product during processing.Typically, the coating layer resulting from application of this blend isnot subject to any curing.

MPH-Extended Release Powder Blend

In order to achieve the desired profile, an oral methylphenidate powderaccording to the invention is a blend of an immediate releasemethylphenidate component and a sustained release methylphenidatecomponent. In one embodiment, the blend contains about 5 to about 30%,or about 10% to about 25%, or about 20% immediate release MPH componentto about 70 to about 95%, about 75% to about 90%, by weight, or about80% by weight sustained release MPH component, based on the total weightof the MPH. However, these ratios can be adjusted as desired.

In one embodiment, the immediate release component is an uncoatedmethylphenidate-resin complex and the sustained release component is abarrier coated methylphenidate-ion exchange resin complex-matrix. Inanother embodiment, an immediate release component can be amethylphenidate-ion exchange resin complex having a coating layer asdescribed herein such that the layer is either thin enough or uncured sothat it provides immediate release. This layer does not interfere withthe immediate release of the drug. For example, such an immediaterelease coated methylphenidate-ion exchange resin complex may containless than about 10% by weight a coating layer, or about 1% to about 8%,by weight, or less. In other embodiments, the immediate releasemethylphenidate-ion exchange resin complex may contain a higher weightpercentage of an aqueous-based coating system such as the polyvinylacetate or ethylcellulose system, if the coating layer is not cured.Optionally, the immediate release component may be in a matrix with apolymer which does not significantly alter its release profile, i.e.,the immediate release methylphenidate-ion exchange resin complex-matrixis an immediate release as defined above. In other words, an “immediaterelease” MPH component preferably releases in less than 1 hour, e.g., assoon as about 45 minutes or as soon as about 30 minutes. Further, in oneembodiment, the MPH immediate release component releases at least about50% of the MPH within about the first hour following administration, andat least about 80% of the MPH within about 90 minutes followingadministration.

In one embodiment, the powder blend also contains a diluent granule,which facilitates reconstitution of the particulate MPH-ion exchangeresin complex, particulate coated MPH-ion exchange resincomplex-matrixes and optionally also provides agents for improving theflow of the powder (e.g., glidants), sweeteners or other flavorings, orsuspending agents.

In one embodiment, a diluent granule used in the invention contains abuffering species used to control pH in the liquid suspensionformulation. Optionally, the diluents granule may contain one or moreother excipients including, e.g., a glidant, a flavoring agent, apreservative, a suspending agent, or mixtures of such excipients.

Suitably, the buffering species is selected so that upon being combinedwith water and any other components of a placebo suspension base, thefinal oral aqueous liquid suspension formulation has a pH in the rangeof about 3.5 to 5, about 4 to about 4.5, or about 4.2. The surfactantmay be a poloxamer. The buffering agent may be selected from one or moreof an acid selected from the group consisting of citric acid, ascorbicacid, acetic acid, tartartic acid, phosphoric acid, a pharmaceuticallyacceptable salt of citric acid, ascorbic acid, acetic acid, tartarticacid, phosphoric acid, or a mixture of an acid or salt. In oneembodiment, the buffering agent is a mixture of sodium citrate andanhydrous citric acid. As described herein, the diluent granules furthercomprise one or more of a poloxamer, a sweetener, and a preservative.

One suitable non-ionic polyoxyethylene-polyoxypropylene blockco-polymers (poloxamers), is represented by the formula:HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H. The examples below illustrate theuse of Poloxamer 188 (available as Pluronic F68 from BASF), where in theformula above “a” is 86 and “b” is 27. However, other suitablepoloxamers or other diluents may be selected. The surfactants useful inthe preparation of the finished compositions of the present inventionare generally organic materials which aid in the stabilization anddispersion of the ingredients in aqueous systems for a suitablehomogenous composition. Preferably, the surfactants of choice arenon-ionic surfactants such as poly (oxyethylene) (20) sorbitanmonooleate and sorbitan monooleate. These are commercially known asTWEENS and SPANS and are produced in a wide variety of structures andmolecular weights.

Whereas any one of a number of surfactants may be used, preferably acompound from the group comprising polysorbate copolymers(sorbitan-mono-9-octadecenoate-poly (oxy-1,2-ethanediyl)) is employed.This compound is also added functions to keep any flavors and sweetenershomogeneously dissolved and dispersed in solution.

Suitable polysorbates include polysorbate 20, polysorbate 40,polysorbate 80 and mixtures thereof. Most preferably, polysorbate 80 isemployed. The surfactant component will comprise from about 0.01 toabout 2.0% w/v of the total composition and preferably will compriseabout 0.1% w/v of the total weight of the composition.

A second emulsifier/surfactant useful in combination with polysorbatesmay be employed and is preferably a poloxamer such as Poloxamer 407.Poloxamer 407 has an HLB (hydrophilic/lipophilic balance) of about 22and is sold under the tradename Pluoronic-127 (BASF-NJ). The twosurfactants can be employed in substantially equivalent amounts. Forexample, the Poloxamer 407 and polysorbate 80 may each be employedtogether at levels of approximately from about 0.02 to about 4.0% w/v ofthe total weight of the formulation.

In the instance where auxiliary sweeteners are utilized, the presentinvention contemplates the inclusion of those sweeteners well known inthe art, including both natural and artificial sweeteners. Thus,additional sweeteners may be chosen from the following non-limitinglist: Water-soluble sweetening agents such as monosaccharides,disaccharides and polysaccharides such as xylose, ribose, glucose,mannose, galactose, fructose, high fructose corn syrup, dextrose,sucrose, sugar, maltose, partially hydrolyzed starch, or corn syrupsolids and sugar alcohols such as sorbitol, xylitol, mannitol andmixtures thereof.

In general, the amount of sweetener will vary with the desired amount ofsweeteners selected for a particular liquid formulation. This amountwill normally be 0.001 to about 90% by weight, per volume of the finalliquid composition, when using an easily extractable sweetener. Thewater-soluble sweeteners described above, are preferably used in amountsof about 5 to about 70% by weight per volume, and most preferably fromabout 10 to about 50% by weight per volume of the final liquidcomposition. In contrast, the artificial sweeteners [e.g., sucralose,acesulfame K, and dipeptide based sweeteners] are used in amounts ofabout 0.005 to about 5.0% and most preferably about 0.01 to about 2.5%by weight per volume of the final liquid composition. These amounts areordinarily necessary to achieve a desired level of sweetness independentfrom the flavor level achieved from flavor oils.

Suitable flavorings include both natural and artificial flavors, andmints such as peppermint, menthol, artificial vanilla, cinnamon, variousfruit flavors, both individual and mixed, essential oils (i.e. thymol,eucalyptol, menthol and methyl salicylate) and the like arecontemplated. The amount of flavoring employed is normally a matter ofpreference subject to such factors as flavor type, individual flavor,and strength desired. Thus, the amount may be varied in order to obtainthe result desired in the final product. Such variations are within thecapabilities of those skilled in the art without the need for undueexperimentation. The flavorings are generally utilized in amounts thatwill vary depending upon the individual flavor, and may, for example,range in amounts of about 0.01 to about 3% by weight per volume of thefinal composition weight.

Useful preservatives include, but are not limited to, sodium benzoate,benzoic acid, potassium sorbate, salts of edetate (also known as saltsof ethylenediaminetetraacetic acid, or EDTA, such as disodium EDTA),parabens (e.g., methyl, ethyl, propyl or butyl-hydroxybenzoates, etc.),and sorbic acid. Amongst useful preservatives include chelating agentssome of which are listed above and other chelating agents, e.g.,nitrilotriacetic acid (NTA); ethylenediaminetetracetic acid (EDTA),hydroxyethylethylenediaminetriacetic acid (HEDTA),diethylenetriaminepentaacetic acid (DPTA), 1,2-diaminopropanetetraaceticacid (1,2-PDTA); 1,3-diaminopropanetetraacetic acid (1,3-PDTA);2,2-ethylenedioxybis[ethyliminodi(acetic acid)] (EGTA);1,10-bis(2-pyridylmethyl)-1,4,7,10-tetraazadecane (BPTETA);ethylenediamine (EDAMINE);trans-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid (CDTA);ethylenediamine-N,N′-diacetate (EDDA); phenazine methosulphate (PMS);2,6-dichloro-indophenol (DCPIP); bis(carboxymethyl)diaza-18-crown-6(CROWN); porphine; chlorophyll; dimercaprol (2,3-dimercapto-1-propanol);citric acid; tartartic acid; fumaric acid; malic acid; and saltsthereof. The preservatives listed above are exemplary, but eachpreservative must be evaluated in each formulation, to assure thecompatibility and efficacy of the preservative. Methods for evaluatingthe efficacy of preservatives in pharmaceutical formulations are knownto those skilled in the art. Preferred preservatives are the parabenpreservatives include methyl, ethyl, propyl, and butyl paraben. Methyland propyl paraben are most preferable. Preferably, both methyl andpropyl paraben are present in the formulation in a ratio of methylparaben to propyl paraben of from about 2.5:1 to about 16:1, preferably9:1.

Optionally, these diluents granules as described herein may form part ofthe MPH extended release powder blend formulation. When present, thediluents granules may be in amount of about 1% by weight to about 90%,or about 10% to about 85%, or about 50% to about 75% by weight of thetotal MPH extended release powder blend.

In one embodiment, the invention provides a methylphenidate ER powderblend containing a barrier coated MPH-ion exchange resin complex-matrixwhich provides a sustained release MPH profile following administration,an uncoated MPH-ion exchange resin complex, or another immediate releaseMPH component, and an optional pH adjuster which is a compound selectedto adjust the pH of a suspension formed by combining water and themethylphenidate ER powder blend to about 3.5 to about 5, about 4 toabout 5, about 4 to about 4.5, or about 4.2. Suitable pH adjusters,including various excipients, may be selected. A pH adjuster may be abuffering agent as described herein.

The ratio of immediate release MPH component to sustained release MPHcomponent may be adjusted as desired by one of skill in the formulationart. In one embodiment, the powder blend contains about 5 to about 20parts by weight MPH in immediate release form and about 95 to about 80parts by weight MPH in the sustained release barrier coated MPH-ionexchange resin complex-matrix, based the total weight of MPH in theblend (i.e., excluding the other components such as the ion exchangeresin, matrix forming polymer and coating). In another embodiment, theMPH ER powder blend contains about 10 to about 30 parts by weight MPH inimmediate release form to about 90 to about 70 parts by weight MPH insustained release barrier coated MPH-ion exchange resin complex-matrix,based upon the total weight MPH. In still a further embodiment, the MPHER powder blend contains about 20 parts by weight MPH in immediaterelease form to about 80 parts by weight sustained release MPH, basedupon the total weight methylphenidate in the powder blend. In oneparticularly preferred embodiment, the immediate release MPH is in acomplex with an ion exchange resin as described herein, optionallyfurther in combination with a matrix forming agent. As described herein,the MPH-ion exchange resin complex and the barrier coated MPH-ionexchange resin complex-matrix are in particulate form and have beenprocesses to ensure that they have a size of about 50 to about 410microns, preferably below about 410 microns. Typically, the average sizeof the particulates is in the range of about 100 microns to about 250microns in size.

In one embodiment, the MPH extended release powder blend is formulatedin a dosage unit which comprises a mixture of granular, barrier coatedMPH-ion exchange resin complex-matrix and uncoated MPH-ion exchangeresin complexes, said granular matrix and complex having a particle sizeranging from about 40 microns to about 410 microns to enhance mouth feel(i.e., texture), or about 50 microns to about 250 microns. Theseparticles may be either regularly or irregularly shaped. In someembodiments, the average particle size of the uncoated MPH-ion exchangeresin complex-matrix or the average particle size of the coated MPH-ionexchange resin complex-matrix is milled to a size of about 100 to about200 microns. These particle sizes may be determined using sieve analysisthrough a sieve shaker having USP standard wire mesh sieves conformingto ASTM specifications. Because the diluent granule is water-soluble,the average size of these granules may be larger than those of theuncoated MPH-ion exchange resin complex and the barrier coated MPH-ionexchange resin complex-matrix. In fact, a larger granule size may bedesirable as the larger surface area of such granules facilitatesdissolution of the diluent granule upon being combined with water. Inone embodiment, the diluent granules are milled through a Fitz mill orother similar device fitted with a 20 mesh screen. Thus, in oneembodiment, the diluent granules are a size below about 850 microns(μm), or below about 840 μm. However, diluent granules may be milled toa smaller size, e.g., about 100 μm to about 200 μm, or to a larger size,e.g., up to about 1000 μm. In one embodiment, the MPH extended releasepowder blend is a homogenous mixture of the granular, barrier coatedMPH-ion exchange resin complex-matrix particles and the granular,uncoated MPH-ion exchange resin complex particles having a size rangingfrom about 100 μm to about 410 μm, in a homogenous admixture withdiluent granules, which may range in size from about 100 μm to about1000 μm.

The MPH extended release powder is stable over a period of at leastabout 18 months at room temperature and has been tested for least 6months under accelerated conditions which are predictive of stableshelf-life for at least about 24 months. As is illustrated in theexamples herein, the potency of the MPH (the active component of thecompositions of the invention) is not directly related to the primarydegradation product. In some embodiments, the MPH extended releasepowder blend has less than 5% loss in potency, preferably less than 3%loss of potency, over a period of at least about 18 months under ambientconditions. While useful for formulation as a solid, the MPH extendedrelease powder blend can be prepared as a suspension for oral deliveryat the time the product needs to be used. This MPH suspension has astable shelf-life under ambient conditions over a period of at leastabout four months at room temperature following admixing with water toform the aqueous extended release MPH suspension. In some embodiment, anaqueous MPH suspension containing the MPH ER powder blend has less than5% loss in potency, preferably a less than 3% loss of potency, over aperiod of at least about 4 months at room temperature.

In one embodiment, the MPH extended release powder blend is formed intoa solid unit dose or a solid preparation. Such solid preparations maytake the form of the powder, optionally with further excipients, loadedinto a foil packet, sachet or the like, or other solid preparations suchas tablets or capsules, etc. In one embodiment, a tablet of theinvention is formulated as an orally disintegrating tablet. Such orallydissolving tablets may disintegrate in the mouth in less than about 60seconds.

In another embodiment, the MPH extended release powder which can bereadily prepared as a suspension for oral delivery. Once prepared as anoral aqueous suspension, the resulting suspension provides a productwhich can be stored for at least about one month, or at least about fourmonths, as a suspension.

Orally Administrable Aqueous MPH Extended Release Suspensions

In one aspect, the invention provides a methylphenidate aqueous extendedrelease oral suspension comprising at least 50% by weight water based onthe total weight of the liquid component of the suspension, whereinextended release is as defined herein (e.g., provides a therapeuticallyeffective plasma profile for about 12 hours). In one embodiment, thesuspension contains at least about 80% by weight based on the totalweight of the suspension. In one embodiment, the suspension has a pH ofabout 3.5 to about 5. In another embodiment, the suspension has a pH ofabout 4 to about 5, or about 4 to about 4.5, or about 4.2.

In one embodiment, where the methylphenidate aqueous extended releaseoral suspension contains at least one coated methylphenidate-ionexchange resin complex-matrix comprising methylphenidate bound to apharmaceutically acceptable ion exchange resin and having a high tensilestrength water-permeable, water-insoluble, non-ionic polymeric barriercoating, the suspension contains at least one other source of a drug(e.g., methylphenidate or a different drug). In one embodiment, the hightensile strength water-permeable, water-insoluble, non-ionic polymericbarrier coating is a cured, coated (Kollicoat® SR30D-plasticizer)barrier coating.

In one embodiment, wherein the methylphenidate aqueous extended releaseoral suspension contains as the sustained release or modified releasecomponent at least one coated methylphenidate-ion exchange resin complexcomprising methylphenidate bound to a pharmaceutically acceptable ionexchange resin and having a high tensile strength water-permeable,water-insoluble, non-ionic polymeric barrier coating, the suspensionalso contains an immediate release methylphenidate component.

In one embodiment, a methylphenidate aqueous extended release oralsuspension has a pharmacokinetic profile in which d-methylphenidate hasan AUC_(0-∞) of about 114 ng-hr/mL to about 180 ng-hr/mL, C_(max) ofabout 11 ng/mL to about 17 ng/mL, T_(max) of about 4 hours to about 5.25hours and T_(1/2) of about 5 hours to about 7 hours following a singleoral administration of an aqueous liquid suspension at a dose equivalentto 60 mg racemic MPH in adults. In one embodiment, the methylphenidateaqueous extended release oral suspension has a pharmacokinetic profileof FIG. 3 and/or a pharmacokinetic profile in which d-methylphenidatehas an AUC_(0-∞) of about 143.65 ng-hr/mL, C_(max) of about 13.61 ng/mL,T_(max) of about 5 hours and T_(1/2) of about 5.65 hours following asingle oral administration of an aqueous liquid suspension at a doseequivalent to 60 mg racemic MPH in adults.

In one embodiment, the methylphenidate aqueous extended release oralsuspension has a pharmacokinetic profile in which methylphenidate has anAUC_(0-∞) of about 137.2 to about 214.4 ng-hr/mL, a C_(max) of about13.6 to about 21.3 ng/mL, T_(max) of about 3 to about 5 hours, or about3.5 to about 4 hours, or about 3.77 hours, following a single oraladministration of an aqueous liquid suspension at a dose equivalent to72 mg racemic MPH in adults. For example, the suspension may have thepharmacokinetic profile of FIG. 1 in which d-methylphenidate has anAUC_(0-∞) of about 171.5 ng-hr/mL and a C_(max) of about 17.0 ng/mLfollowing a single oral administration of an aqueous liquid suspensionat a dose equivalent to 72 mg racemic MPH in adults.

In one embodiment, the methylphenidate aqueous extended release oralsuspension contains methylphenidate selected from racemicmethylphenidate and/or dexmethylphenidate.

In another embodiment, the invention provides an aqueous liquidsuspension formulation reconstituted from a powder blend. The powderblend typically contains granules of a size ranging from about 50 toabout 410 μm in size, which granules are a blend of uncoatedmethylphenidate-ion exchange resin complex, a barrier coatedmethylphenidate-ion exchange resin complex-matrix, and, optionally, adiluent granule. Where a diluent granule is present in the MPH ER powderblend, upon admixing with the aqueous liquid suspension, the diluentgranule is dissolved and forms a solution, whereas the uncoated MPH-ionexchange resin complex and the coated MPH-ion exchange resincomplex-matrix are suspended. Optionally, a pH adjuster may be providedby the diluent granule or this function may be provided by a separatecomponent when the powder is combined to form the suspension. Such a pHadjuster is a component which adjusts the pH of the suspension to therange of about 3.5 to about 5, about 4 to about 5, about 4 to about 4.5,or about 4.2.

Optionally, one or more desired excipients, including, e.g., flavorants,sweeteners, or preservatives, or other excipients may be added to thesuspension.

In one embodiment, an orally administrable aqueous suspension isobtained by dispersing the MPH extended release powder blend in asuitable aqueous vehicle (i.e., water). When reference is made to anoral aqueous suspension, the term encompasses products containing theMPH ER powder blend suspended in a liquid base which contains more thanabout 50% water. In some embodiments, the liquids in the aqueoussuspension base contain at least about 80% water, at least about 90%water, at least about 95% water, at least about 99% water, or 100%water. Suitably, the suspension has a pH in the range of about 3.5 toabout 5, preferably, about 4 to about 4.5 and more preferably about 4.2.In some embodiments, the liquid suspension contains at least 80% waterand the resulting formulation is stable for at least about one monthfollowing combination of the components of the MPH powder blend and theaqueous suspension. In some embodiments, the MPH aqueous ER suspensionis stable for at least about four months.

The MPH extended release aqueous suspension product permits ready dosetitration, i.e., adjusting the dose of a medication based on recommendeddose range and frequency until the desired therapeutic effect isachieved. With the MPH ER aqueous suspension, physician can titrate asrapidly or slowly as desired, using any dose increment; in contrast,with tablets and other similar solid formulations, the dose increment islimited. In addition, a physician can readily customize the dose so itis precisely right for the patient. This is particularly desirably, asmany patients experience some side effects (i.e., difficulty sleeping orloss of appetite) as they approach or slightly exceed the therapeuticdose. Since most doctors prefer extended release dosage forms for thesepatients (so they don't need to take a 2^(nd) dose during the day),customizing dose and good dose titration was difficult using theproducts available prior to this invention. The present product willprovide an extended release aqueous suspension MPH medication, making ituseful for titration and once daily dosing.

In one embodiment, the MPH ER powder blend provides a pharmacokineticprofile in which d-methylphenidate has AUC_(0-∞) (ng-hr/mL) of about 114ng-hr/mL to about 180 ng-hr/mL, C_(max) (ng/mL) is about 11 (ng/mL) toabout 17 (ng/mL), T_(max) (hr) is about 4 hours to about 5.25 hours andT_(1/2) (hr) is about 5 hours to about 7 hours following a single oraladministration of an aqueous liquid suspension containing the MPH ERpowder blend suspended therein at a dose equivalent to about 60 mgracemic methylphenidate hydrochloride in adults. In one embodiment, theMPH ER powder blend contains racemic methylphenidate. In anotherembodiment, the MPH ER powder blend contains dexmethylphenidate. Instill another embodiment, the MPH ER powder blend contains both racemicmethylphenidate and dexmethylphenidate. In one embodiment, an MPH ERpowder blend comprising an immediate release methylphenidate component,a sustained release barrier coated methylphenidate-ion exchange resincomplex-matrix, and an optional water soluble buffering agent, providethis pharmacokinetic profile. In one embodiment, the blend containsabout 5 to about 30%, or about 10% to about 25%, or about 20% immediaterelease MPH component to about 70 to about 95%, about 75% to about 90%,by weight, or about 80% by weight sustained release MPH component, basedon the total weight of the MPH. In one embodiment, the immediate releasecomponent is an uncoated MPH-ion exchange resin complex may provide theimmediate release component. However, optionally, other immediaterelease forms of the MPH may be utilized in a formulation of theinvention. Where the immediate release methylphenidate component is anuncoated methylphenidate-ion exchange resin complex, it is optionally incombination with a hydrophilic or hydrophobic polymeric matrix formingcomponent as defined herein. The sustained release MPH component is abarrier coated MPH-ion exchange resin complex-matrix. In one embodiment,the barrier coating is a water-permeable, high tensile strength, waterinsoluble, barrier coating comprising a polyvinylacetate polymer and aplasticizer. In another embodiment, the barrier coating is anethylcellulose barrier coating. In still another embodiment, the coatingis a poly (ethyl acrylate-co-methylmethacrylate-co-trimethylammoniumethylmethacrylatechloride) polymer.Depending upon the barrier coating selected, curing is optional, asdescribed in more detail in this specification, which discussion isincorporated by reference herein. In one embodiment, the barrier coatingis cured and comprises a polyvinylacetate, a stabilizer, a surfactant,and a plasticizer. In one embodiment, the barrier coat comprises about2.5 to about 15% of plasticizer, about 70 to about 90% polyvinylacetate,about 5 to about 10% polyvinylpyrrolidone, and about 0.1 to about 1%surfactant. In a further embodiment, the plasticizer is triacetin andthe surfactant is sodium lauryl sulfate. In still a further embodiment,the barrier coat comprises about 20% to about 45% by weight of thecoated methylphenidate-ion exchange resin complex-matrix. In anotherembodiment, the coated methylphenidate ion exchange resin complex-matrixcomprises a hydrophilic polymer in an amount of about 5 to about 20% byweight, based on the weight of the uncoated methylphenidate-ion exchangeresin complex-matrix. In still a further embodiment, the hydrophilicpolymer is polyvinylpyrrolidone. In another embodiment, the coatedmethylphenidate ion exchange resin complex-matrix comprises ahydrophobic polymer or co-polymer in an amount of about 5 to about 20%by weight, based on the weight of the (uncoated or precoated)methylphenidate-ion exchange resin complex-matrix. In still a furtherembodiment, the hydrophobic polymer comprises polyvinylacetate.Optionally, in any of the embodiments described herein, the MPH ERpowder blend may contain water-soluble diluent granules in order tofacilitate suspension and provide a powder blend to which only waterneed be added to provide a final suspension suitable for administrationto a patient. The pH adjuster may be a buffering agent which may includeone of the following or may be selected from the group consisting of oneor more of a pharmaceutically acceptable acid selected from the groupconsisting of citric acid, ascorbic acid, acetic acid, tartartic acid,phosphoric acid, a pharmaceutically acceptable salt of citric acid,ascorbic acid, acetic acid, tartartic acid, phosphoric acid, or amixture of said pharmaceutically acceptable acid or salt. In oneembodiment, the buffering agent contains a mixture of sodium citrate andanhydrous citric acid. In another embodiment, the diluent granulesfurther comprise one or more of a surfactant, a sweetener, and apreservative. In a further embodiment, the diluent granules comprise apoloxamer.

In one embodiment, the powder blend is reconstituted into an aqueousliquid MPH extended release suspension formulation having apharmacokinetic profile in which d-methylphenidate has AUC_(0-∞) isabout 143.65, C_(max) (ng/mL) is about 13.61, T_(max)(hr) is about 5 andT_(1/2) (hr) is about 5.65.

In one embodiment, an MPH ER powder blend having the following formulahas this profile a cured, (Kollicoat® SR30D-plasticizer) barrier coated(30% weight gain) methylphenidate-ion exchange resincomplex-polyvinylpyrrolidone (about 8%) matrix,) an uncoatedmethylphenidate-ion exchange resin complex, in which the weight ratio ofimmediate extended release MPH to sustained release MPH is approximately80 parts by weight to approximately 20% parts. In one embodiment, thepowder blend is reconstituted into an aqueous liquid MPH extendedrelease suspension formulation having a pharmacokinetic profile in whichd-methylphenidate has AUC_(0-∞) is about 143.65, C_(max) (ng/mL) is13.61 (42.56), T_(max) (hr) is 5.00 (1.67-6.00) and T_(1/2) (hr) is 5.65(15.01) at a dose equivalent to about 60 mg racemic methylphenidatehydrochloride in adults.

In still another embodiment, the present invention provides a single MPHextended release product which provides immediate release and furtherprovides the pharmacokinetic profile of a twelve-hour sustained releasecomposition. In one embodiment, the extended release contains animmediate release component which is bioequivalent to a commerciallyavailable immediate release formulation (e.g., Methylin) and a componentproviding a sustained release MPH profile.

In one embodiment, the oral MPH aqueous ER suspension has a pH in therange of about 3.5 to about 5, preferably, about 4 to about 4.5 and morepreferably about 4.2. In some embodiments, the aqueous suspensioncontains at least 80% water and the resulting formulation is stable forat least about one month following combination of the MPH ER powderblend and the suspension base. In other embodiments, the Aqueoussuspension is stable at a pH of about 4 to about 4.5 for at least aboutfour months following preparation of the suspension containing the MPHER powder blend.

Uses

An aqueous MPH extended release composition of the invention may beorally administered to a patient having a disorder treatable by MPH.These include disorders for which regulatory approval has been grantedin the US or other jurisdiction in which the drug is being administeredand which requires regulatory approval. For example, MPH is currentlyapproved for treatment of Attention Deficit Hyperactivity Disorder(ADHD), postural orthostatic tachycardia syndrome, and narcolepsy. MPHhas also been described in patent applications and in the literature asbeing useful for treatment of such disorders including, but are notlimited to, behavioral disorders, treatment-resistant cases of lethargy,depression, neural insult, obesity, and rarely other psychiatricdisorders such as obsessive-compulsive disorder, Attention DeficitDisorder, depression, specific dyslexias, brain dysfunction, cognitivedecline in AIDS and AIDS related conditions, alertness in geriatric,Alzheimer's patients, in recovery in stroke victims.

Thus, the invention provides a method of treating one or more of theabove disorders for a period of at least twelve hours by administeringan aqueous oral liquid MPH extended release composition based on thereconstituted MPH extended release powder blend of a barrier coatedmethylphenidate-ion exchange resin complex-matrix and MPH immediaterelease component (e.g., an uncoated MPH-ion exchange resin complex),e.g., a liquid suspension product having a pH in the range of about 3.5to about 5, about 4 to about 5, about 4 to about 4.5 or about 4.2.Following administration of a single dose of the oral MPH composition, atherapeutically effective amount of MPH is reached as soon as about 45minutes or earlier. In one embodiment, the average peak plasmaconcentration from a single oral dose of the MPH extended releaseaqueous suspension is reached about two to about five hours afteradministration.

The concentration of methylphenidate is variable and may be determinedby the desired dosage and volume. For example, an amount ofmethylphenidate equivalent to 1 mg/mL methylphenidate HCl may be used toprovide a 5 mg oral dose per teaspoon, and an amount of methylphenidateequivalent to 2 mg/mL methylphenidate HCl suspension may yield a 10 mgoral dose per teaspoon. These concentrations correspond to two dosagescurrently available, but can go higher. However, since themethylphenidate is delivered in a solution, the dosage can be easilymanipulated to prescribe a non-standard dosage. The concentration ofmethylphenidate may be equivalent to about 0.1 mg/mL to about 10.0 mg/mLmethylphenidate HCl.

A composition of the invention is formulated to deliver MPH is, mostdesirably, in dosages ranging from about 1 mg up to about 100 mg perday, preferably from about 10 to about 75 mg per day, or in about 18,25, or 60 mg doses [based on equivalence to racemic methylphenidate HCl]although variations will necessarily occur depending upon the weight andcondition of the subject being treated and the particular route ofadministration chosen. Actual dosages of dexmethylphenidate may be athalf the amounts of racemic methylphenidate. Variations may neverthelessoccur depending upon the weight and condition of the persons beingtreated and their individual responses to said medicament.

As described herein, the MPH extended release composition of theinvention permits the compounds to be dosed orally twice-a-day at12-hour intervals. However, depending upon the patient, smaller dosesmay be delivered at intervals during the day. Other patients may take asingle dose in the morning and forego dosage in the evening.

The following examples are illustrative only and are not intended to bea limitation on the present invention.

EXAMPLES

Examples 1 to 5 illustrate preparation of powders which arereconstitutable for methylphenidate-ion exchange resin oral suspension,equivalent to 25 mg methylphenidate HCl per 5 mL.

Example 1 Methylphenidate ER Powder for Aqueous Oral Suspension

Example 1 illustrates preparation of an oral suspension compositionreconstituted from a methylphenidate (MPH) extended release (ER) powder.In this example, the MPH ER powder blend is a combination of (i) anuncoated methylphenidate-ion exchange resin, (ii) a cured, coated(polyvinylacetate-plasticizer, 30% weight gain) methylphenidate-ionexchange resin complex-hydrophilic polymer matrix, and (iii) diluentgranules.

A. Uncoated Methylphenidate-Ion Exchange Resin Complex

Ingredients Quantity Methylphenidate HCl 3100 g Amberlite ® IRP69 7693 gSodium Polystyrene Sulfonate Resin Purified Water* Qs* *Removed duringprocessing

The uncoated methylphenidate-resin complex was prepared by first adding80 L of Purified Water in to the vessel and methylphenidate HCl wasdissolved by continuous mixing. Sodium polystyrene sulfonate ionexchange resin [Amberlite® IRP 69; Rohm and Haas] was dispersed in thesolution with continuous mixing, which was continued for 60 minutes topermit time for the methylphenidate and ion exchange resin to form acomplex. Water was removed by filtration process followed by rinsingtwice using purified water; during which process displaced salt ions(from the MPH or the resin) are also removed. Wet resin complex was thendried until moisture content was 3% to 7%. This driedmethylphenidate-ion exchange resin complex was passed through a CO-MILdevice fitted with a standard 40 mesh screen (i.e., the granules passingthrough have a particulate size below about 410 μm). This was theparticulate uncoated methylphenidate-resin complex (methylphenidatepolistirex).

B. Precoated Methylphenidate-Ion Exchange Resin Complex-Matrix

Ingredients Quantity Uncoated Methylphenidate—Ion Exchange Resin 8500 gComplex of Part A Kollidon ® K30 polyvinylpyrrolidone (PVP)  657 gPurified water* 2629 g Purified Water* Qs* *Removed during processing

In a separate container polyvinylpyrrolidone (purchased as Kollidon® K30from BASF) was dissolved in 2629 g of purified water (PVP solution).Uncoated methylphenidate-resin complex prepared according to Part A wastreated with the povidone solution until a 7.73% polymer weight gain wasachieved and with continuous mixing to form a uniform mass. The wet masswas dried until the moisture content was between 15-25%. Semi-driedmaterial was then passed through a CO-MIL device fitted with a standard40 mesh screen (about 410 μm). Milled material was further dried untilmoisture content was 3% to 7%. Dried material was again passed through aCO-MIL device fitted with a standard 40 mesh screen (about 410 μm). Thiswas the precoated methylphenidate-ion exchange resin complex-(PVP)matrix.

C. Coated Methylphenidate-Ion Exchange Resin Complex-Matrix

Ingredients Quantity Precoated Methylphenidate—Ion Exchange Resin 3900 gComplex—Matrix of Part B Kollicoat ® SR30D (30% w/w aqueous dispersion*3714 g Triacetin (plasticizer)  56 g Purified Water* 2080 g *Removedduring processing

The precoated methylphenidate-ion Exchange Resin complex-matrix wascoated as follows. The coating solution was prepared by mixingtriacetin, purified water and Kollicoat® SR30D (BASF, aqueous dispersionwith 30% solids content, containing 27% Polyvinylacetate, 2.7%polyvinylpyrrolidone, 0.3% sodium lauryl sulfate) in a separatecontainer. The coating process was performed in a fluid bed processorequipped with Wurster column by applying coating solution on to 3900grams of the precoated methylphenidate-ion exchange resin complex-matrixprepared as described in Part B above, until 30% weight gain wasachieved. The (Kollicoat® SR30D-triacetin) coated methylphenidate-ionexchange resin complex-matrix was cured in a hot air oven at 60° C. for5 hours. The cured coated methylphenidate-ion exchange resincomplex-matrix was passed through a standard 40 mesh screen.

D. Diluent Granules

Ingredient Quantity Poloxamer 188  125 g Purified water*  1764 g Sugar34418 g Sodium citrate  965 g Anhydrous citric acid  1290 g Sodiumbenzoate  500 g Sucralose  200 g *Removed during processing

In a separate container, Poloxamer® 188 [BASF] was dissolved in purifiedwater (poloxamer solution). Sugar, sodium citrate, anhydrous citricacid, sodium benzoate, and sucralose were added into high sheargranulator and granulation process was performed using Poloxamersolution. Wet granules were dried using fluid bed drier until moisturelevel was below 1.50%. Dried granules were then milled through Fitz millequipped with 20 mesh screen (openings of about 850 m). This was theDiluent Granules.

E. Methylphenidate ER Powder Blend

Ingredient Quantity Diluent Granules 34066 g Starch  3134 g Xanthan gum 341 g Talc  455 g Banana flavor  341 g Silicon dioxide  455 g Sugar 1359 g Coated Methylphenidate—Ion  4499 g exchange Resin Complex—MatrixUncoated Methylphenidate—Ion  770 g Exchange Resin Complex

Diluent granules prepared according to Part D were loaded in to a ‘V’blender. Starch, xanthan gum, talc, banana flavor, silicon dioxide,sugar, coated methylphenidate-ion exchange resin complex-matrix preparedaccording to Part C, and uncoated methylphenidate-ion exchange resincomplex prepared as described in Part A (weight ratio of approximately80 parts by weight coated to approximately 20% parts by weight uncoatedmethylphenidate-ion exchange resin complex, based on the weight ratio ofthe methylphenidate in each component) were loaded into a ‘V’ blenderand mixed for 10 minutes.

Following mixing, the blend of the uncoated methylphenidate-ion exchangeresin complex and coated methylphenidate-ion exchange resincomplex-matrix (Polistirex ER Powder blend) was filled into anappropriate container which, when reconstituted with purified water,achieved a concentration equivalent to 25 mg methylphenidatehydrochloride per 5 mL. When water is added, the resulting oral liquidsuspension has a pH in the range of about 4.2.

In an initial study, the pharmacokinetic parameters of the 25 mgmethylphenidate/5 mL suspension formulation of this example were studiedfrom 0 to 24 hours. The mean plasma d-methylphenidate concentration isshown in FIG. 1. This formulation was administered as a single oral doseof 72 mg, and compared to a commercially available solid extendedrelease methylphenidate formulation (Concerta®, administered as a 72 mgdose (four 18 mg tablets). The mean T_(max) for this formulation is 3.77hours.

Summary of Methylphenidate Pharmacokinetic Parameters 90% Geometric T/RConfidence Intra- Mean Ratio Limits Subj MPH TEST Ref (%) Lower Upper CV(%) C_(max)  17.02  17.36  98.03  90.73 105.92 9.89 (ng/mL) AUC_((0-t))160.13 182.90  87.55  82.44  92.98 7.67 (ng-h/mL) AUC_((0-∞)) 171.50188.54  90.96  85.38  96.92 8.09 (ng-h/mL) AUC_(pR)  91.50 188.54 127.24119.20 135.82 8.33 (ng-h/mL) AUC_(pR) is the area under the curve to thepopulation median T_(max) of the reference formulation. AUC_(0-t) is thearea under the plasma/serum/blood concentration-time curve from timezero to time t, where t is the last time point with measurableconcentration for individual formulation. T/R ratio refers to the testformulation (methylphenidate polistirex 25 mg/5 mL ER oral suspension)to reference (R) formulation. Intra-subject CV % refers to the geometric(CV) coefficient of variation between subjects.

The average peak plasma concentration from a single oral dose underfasting conditions is reached in 2 to 5 hours. The 12-hour plasmaconcentration was 5 ng/mL. Based on the pharmacokinetic study, rapidonset of action was observed at the first measured time point (45minutes) and an extended release profile (i.e., about 12 hours) wasobserved in adult ADHD patients.

F. Chemical Stability

The chemical stability of the methylphenidate ER powder of theinvention, prepared as described in this Example, following admixing inwater at the varying concentrations shown in the table below to form asuspension have a pH of 4.2 was assessed. The resulting methylphenidateER suspension shows that the resulting product maintains about 98% ofits initial potency with its primary degradant(theo-α-phenyl-1-piperidineacetic acid hydrochloride) of not more than0.7% after 4 months of storage of the reconstituted powder blend atambient condition. The chemical stability data is show in the followingtable.

Condition % Potency % Impurity* Initial 99 0.1 2 months 99 0.4 3 months98 0.7 4 months 97 0.7 *Theo-α-phenyl-2-piperidineacetic acidhydrochloride

These results show that the composition of increase in impurities is notdirectly linked to loss of potency.

Example 2 Methylphenidate ER Powder for Aqueous Oral Suspension

Example 2 illustrates preparation of an oral suspension compositionreconstituted from a methylphenidate (MPH) extended release (ER) powderfor oral suspension. In this example, the MPH ER powder blend is acombination of (i) an uncoated methylphenidate-ion exchange resin, (ii)a cured, coated (polyvinylacetate-plasticizer, 45% weight gain)methylphenidate-ion exchange resin complex-hydrophilic polymer matrix,and (iii) diluent granules.

A. Uncoated Methylphenidate-Ion Exchange Resin Complex

Ingredients Quantity Methylphenidate HCl   100 g Amberlite ® IRP69235.75 g Sodium Polystyrene Sulfonate Resin Purified Water* Qs* *Removedduring processing

The methylphenidate-ion exchange resin complex was prepared by firstadding 2 L of purified water into the vessel and dissolvingmethylphenidate HCl in the water by continuous mixing. The Amberlite®IRP69 sodium polystyrene sulfonate resin was dispersed into the solutionwith continuous mixing, which was continued for 120 minutes. Water wasremoved by filtration process followed by rinsing twice using purifiedwater. The wet resin complex was then dried until the moisture contentwas 3 to 7%. This dried methylphenidate-ion exchange resin complex waspassed through a CO-MIL device fitted with a standard 40 mesh screen.This was the particulate uncoated methylphenidate-ion exchange resin(methylphenidate polistirex).

B. Precoated Methylphenidate-Ion Exchange Resin Complex-Matrix

Ingredients Quantity Methylphenidate HCl    650 g Amberlite IRP 691613.03 g Sodium Polystyrene Sulfonate Resin Purified Water* Qs*Kollidon ® K30  547.09 g Purified water*    182 g Purified Water* Qs**Removed during processing

A methylphenidate-ion exchange resin complex was prepared by firstadding 10 L of purified water into the vessel and adding inmethylphenidate HCl which was dissolved by continuous mixing. Sodiumpolystyrene sulfonate resin [Amberlite IRP69, Rohm & Haas] was dispersedinto the solution with continuous mixing, which was continued for 60minutes. Water was removed by filtration process followed by rinsingtwice using purified water. Wet resin complex was then dried untilmoisture content was 15 to 25%. In a separate container Kollidon® K30(BASF) was dissolved in 547.09 g of purified water (PVP solution). Thepartially dried methylphenidate-ion exchange resin complex was treatedwith the PVP solution with continuous mixing to form a uniform wet massof the methylphenidate-ion exchange resin-PVP matrix. The uniform wetmass was dried until the moisture content was 15 to 25%. Semi-driedmethylphenidate-ion exchange resin complex-matrix was then passedthrough a CO-MIL™ device fitted with a standard 40 mesh screen. Milledmethylphenidate-ion exchange resin matrix was further dried untilmoisture content was 3 to 7%. Dried material was again passed through aCO-MIL™ device fitted with a standard 40 mesh screen. This was theparticulate precoated methylphenidate-ion exchange resin matrix.

C. Coated Methylphenidate-Ion Exchange Resin Complex-Matrix

Precoated methylphenidate ion exchange resin   600 g complex—matrix(from Part B) Kollicoat ® SR30D** 952.35 g Triacetin  14.25 g PurifiedWater*  533.4 g *Removed during processing **30% w/w aqueous dispersion

The precoated methylphenidate-ion exchange resin complex-matrix wascoated as follows. The coating solution was prepared by mixingtriacetin, purified water and the Kollicoat® SR30D polyvinyl acetatedispersion (BASF) in a separate container. The coating process wasperformed in a fluid bed processor equipped with Wurster column byapplying coating solution onto precoated methylphenidate-ion exchangeresin complex-matrix prepared according to Part B that resulted in 45%weight gain. The (Kollicoat® SR30D-triacetin) coated methylphenidate-ionexchange resin complex-matrix was cured in a hot air oven at 60° C. for5 hours. The cured coated methylphenidate-ion exchange resincomplex-matrix was passed through a standard 40 mesh screen.

D. Diluent Granules

Ingredient Quantity Poloxamer 188   2.25 g Purified water*    50 g Sugar625.97 g Sodium citrate  17.38 g Anhydrous citric acid  23.22 g Sodiumbenzoate    9 g *Removed during processing

In a separate container, the Poloxamer 188 was dissolved in purifiedwater (poloxamer solution). Sugar, sodium citrate, anhydrous citricacid, and sodium benzoate were added into a high shear granulator and agranulation process was performed using the Poloxamer solution. Wetgranules were dried using fluid bed drier until moisture level was below1.5%. Dried granules were then milled through a Fitz mill equipped with20 mesh screen to form the Diluent Granules.

E. Methylphenidate ER Powder Blend

Ingredient Quantity Diluent Granules 37.16 g Starch 5.716 g Xanthan Gum0.628 g Coated Methylphenidate—Ion 6.073 g Exchange Resin Complex—MatrixUncoated Methylphenidate—Ion 0.424 g Exchange Resin Complex

Diluent Granules prepared according to Part D were mixed with starch,xanthan gum, coated methylphenidate-ion exchange resin complex-matrixprepared as described in part C of this Example, and UncoatedMethylphenidate-Ion Exchange Resin Complex prepared as described in PartA of this example. The powder blend contained a weight ratio of about90% by weight methylphenidate in sustained release form (coatedcomplex-matrix) to about 10% by weight methylphenidate in immediaterelease form (uncoated methylphenidate-ion exchange resin complex),based upon the total weight of the methylphenidate in the formulation.

The Methylphenidate ER Powder blend was filled into an appropriatecontainer which, when reconstituted with purified water, achieved aconcentration equivalent to 25 mg methylphenidate hydrochloride per 5mL.

Example 3 Methylphenidate ER Powder for Aqueous Oral Suspension

In this example, the MPH ER powder blend is a combination of (i) anuncoated methylphenidate-ion exchange resin, (ii) a cured, barriercoated (polyvinylacetate-plasticizer, 35% weight gain)methylphenidate-ion exchange resin complex-hydrophobic polymer matrix,and (iii) diluent granules.

A. Uncoated Methylphenidate-Ion Exchange Resin Complex

Ingredients Quantity Methylphenidate HCl   100 g Amberlite ® IRP69 248.2g Sodium Polystyrene Sulfonate Resin Purified Water* Qs* *Removed duringprocessing

The methylphenidate-ion exchange resin complex was prepared by firstadding 1.5 L of purified water into the vessel and dissolvingmethylphenidate HCl therein by continuous mixing. Amberlite® IRP69 ionexchange resin was dispersed into the solution with continuous mixing,which mixing was continued for 60 minutes. Water was removed byfiltration process followed by rinsing twice using purified water. Thewet resin complex was then dried until moisture content was 3% to 7%.Dried drug-resin complex was passed through a CO-MIL device fitted witha standard 40 mesh screen. This was the particulate uncoatedmethylphenidate-ion exchange resin complex.

B. Precoated Methylphenidate Ion Exchange Resin Complex-Matrix

Ingredients Quantity Methylphenidate HCl    650 g Amberlite ® IRP 691613.03 g Sodium Polystyrene Sulfonate Resin Purified Water* Qs*Kollicoat ® SR 30D**  606.7 g Purified water*    505 g Purified Water*Qs* *Removed during processing **30% w/w aqueous dispersion

A methylphenidate-ion exchange resin complex was prepared by firstadding 10 L of purified water in to the vessel and dissolvingmethylphenidate HCl therein by continuous mixing. Amberlite® IRP69 wasdispersed in the solution with continuous mixing, which was continuedfor 60 minutes. Water was removed by filtration process followed byrinsing twice using purified water. Wet resin complex was then drieduntil moisture content was 15% to 20%. In a separate containerKollicoat® SR 30D [27% polyvinylacetate, 2.7% polyvinylpyrrolidone, 0.3%sodium lauryl sulfate] was mixed with 505 g of purified water (KollicoatDispersion). The partially dried resin complex was combined with theKollicoat Dispersion with continuous mixing to form a uniform wet massof the methylphenidate-ion exchange resin complex-Kollicoat® SR30Dmatrix. The wet mass was dried until the moisture content was 10% to15%. Semi-dried methylphenidate-ion exchange resin complex-matrix wasthen passed through a CO-MIL device mill fitted with a standard 40 meshscreen. The milled methylphenidate-ion exchange resin complex-matrix wasfurther dried until moisture content was 3% to 7%. Driedmethylphenidate-ion exchange resin complex-matrix was passed through aCO-MIL fitted with a standard 40 mesh screen. This was the precoatedmethylphenidate-ion exchange resin complex-matrix.

C. Coated Methylphenidate-Ion Exchange Resin Complex-Matrix

Ingredients Quantity Precoated Methylphenidate - Ion Exchange 600 gResin Complex - Matrix (from Part B) Kollicoat ® SR30D** 761.88 gTriacetin 11.40 g Purified Water* 426.72 g *Removed during processing**30% w/w aqueous dispersion

The precoated methylphenidate-ion exchange resin complex-matrix wascoated as follows. The coating solution was prepared by mixingtriacetin, purified water and Kollicoat® SR30D (aqueous dispersion, 30%solids) in a separate container. The coating process was performed in afluid bed processor equipped with Wurster column by applying coatingsolution onto precoated methylphenidate-ion exchange resincomplex-matrix of part B that resulted in 35% weight gain. The coatedmethylphenidate-ion exchange resin complex-matrix was cured in a hot airoven at 60° C. for 5 hours. The cured coated methylphenidate-ionexchange resin complex-matrix was again passed through a standard 40mesh screen.

Ingredient Quantity Poloxamer ® 188 2.25 g Purified water* 50 g Sugar625.97 g Sodium citrate 17.38 g Anhydrous citric acid 23.22 g Sodiumbenzoate 9 g *Removed during processing

D. Diluent Granules

In a separate container, Poloxamer™ was dissolved in purified water(poloxamer solution). Sugar, sodium citrate, anhydrous citric acid, andsodium benzoate were added into a high shear granulator and agranulation process was performed using the Poloxamer solution. Wetgranules were dried using fluid bed drier until moisture level was below1.5%. Dried granules were then milled through Fitz mill equipped with 20mesh screen. This was the Diluent Granules.

E. Methylphenidate ER Powder Blend

Ingredient Quantity Diluent Granules 75.45 g Starch 11.43 g Xanthan Gum1.256 g Coated Methylphenidate - Ion Exchange 10.144 g Resin Complex -Matrix Uncoated Methylphenidate - Ion 1.724 g Exchange Resin Complex

Diluent granules prepared as described in Part D were mixed with starch,xanthan gum, coated methylphenidate-ion exchange resin complex-matrixprepared as described in Part C and uncoated Methylphenidate-IonExchange Resin Complex prepared as described in Part A. The ratio ofimmediate release methylphenidate (uncoated complex) and sustainedrelease methylphenidate (coated complex-matrix) was 10 parts by weightimmediate release methylphenidate to 90 parts by weight sustainedrelease methylphenidate, based on the total weight of methylphenidate inthe formulation. The Methylphenidate Polistirex ER Powder blend wasfilled into an appropriate container which, when reconstituted withpurified water, achieved a concentration equivalent to 25 mgmethylphenidate hydrochloride per 5 mL.

Example 4 Methylphenidate ER Powder for Aqueous Oral Suspension

In this example, the MPH ER powder is a combination of (i) an uncoatedmethylphenidate-ion exchange resin (immediate release MPH component),(ii) a cured, coated (ethylcellulose, 30% weight gain)methylphenidate-ion exchange resin complex-hydrophilic polymer matrix(sustained release MPH component), and (iii) diluent granules.

A. Uncoated Methylphenidate-Ion Exchange Resin Complex

Ingredients Quantity Methylphenidate HCl 3100 g Amberlite ® IRP69 7693 gSodium Polystyrene Sulfonate Resin Purified Water* Qs* *Removed duringprocessing

The methylphenidate-ion exchange resin complex was prepared by firstadding 80 L of purified water in to the vessel and methylphenidate HClwas dissolved therein by continuous mixing. Amberlite™ IRP69 ionexchange resin was dispersed with continuous mixing, which mixing wascontinued for 60 minutes. Water was removed by filtration processfollowed by rinsing twice using purified water (40 L). The wetmethylphenidate-ion exchange resin complex was then dried until moisturecontent was 3 to 7%. Dried methylphenidate-ion exchange resin complexwas passed through the CO-MIL device fitted with a standard 40 meshscreen. This was the Uncoated Methylphenidate-ion exchange resincomplex.

B. Precoated Methylphenidate-Ion Exchange Resin Complex-Matrix

Ingredients Quantity Uncoated Methylphenidate - Ion Exchange 8500 gResin Complex (From Part A) Kollidon ® K30 657 g Purified water* 2629 gPurified Water* Qs* *Removed during processing

In a separate container Kollidon K30 was dissolved in 2629 g of PurifiedWater (PVP solution). Uncoated Methylphenidate-ion exchange resincomplex prepared as described in Part A was treated with the PVPsolution until a 7.73% polymer weight gain was achieved and withcontinuous mixing to form a uniform mass. Wet mass was dried until themoisture content was 15% to 25%. Semi-dried material was then milledusing a CO-MIL device fitted with a standard 40 mesh screen. Milledmaterial was further dried until moisture content was 3 to 7%. Driedmaterial was again passed through a CO-MIL device fitted with a standard40 mesh screen. This was the precoated methylphenidate ion exchangeresin complex-matrix.

C. Coated Methylphenidate-Ion Exchange Resin Complex-Matrix

Ingredients Quantity Precoated Methylphenidate - Ion Exchange 600 gResin Complex Matrix (From Part B) Surelease ® ethylcellulose dispersion780 g Purified Water* 520 g *Removed on processing **28% w/w aqueousdispersion

The precoated methylphenidate-ion exchange resin complex-matrix wascoated as follows. The coating solution was prepared by mixing purifiedwater and Surelease™ in a separate container. Surerelease™ is availablefrom Colorcon as an aqueous ethyl cellulose dispersion containing water(70.6% w/w), ethylcellulose (18.8% w/w), ammonium hydroxide (4.4% w/w),a medium chain triglyceride (4.0% w/w), and oleic acid (2.2% w/w), witha viscosity of 20 cps. The coating process was performed in a fluid bedprocessor equipped with Wurster column by applying coating solution onto the precoated methylphenidate ion exchange resin complex-matrixprepared as described in Part B above that resulted in 30% weight gain.The coated methylphenidate ion exchange resin complex-matrix was curedin a hot air oven at 60° C. for 5 hours. The cured coatedmethylphenidate-ion exchange resin complex-matrix was again passedthrough a standard 40 mesh screen.

C. Diluent Granules

Ingredient Quantity Poloxamer ™ 188 30 g Purified water* 600 g Sugar8260.63 g Sodium citrate 231.76 g Anhydrous citric acid 309.6 g Sodiumbenzoate 120 g Sucralose 48 g *Removed during processing

In a separate container, the surfactant was dissolved in purified water(poloxamer solution). Sugar, sodium citrate, anhydrous citric acid,sodium benzoate, and sucralose were added into a high shear granulatorand granulation was performed using the Poloxamer solution. Wet granuleswere dried using fluid bed drier until moisture level was below 1.50%.Dried granules were then milled through Fitz mill equipped with 20 meshscreen. This was the Diluent Granules.

E. Methylphenidate ER Powder Blend

Ingredient Quantity Diluent Granules 480 g Starch 44.16 g Xanthan gum4.8 g Talc 6.4 g Banana flavor 4.8 g Silicon dioxide 6.4 g Sugar 19.46 gCoated Methylphenidate Ion Exchange 62.78 g Resin Complex - MatrixUncoated Methylphenidate - Ion 11.2 g Exchange Resin Complex

The Diluent granules of Part D above were loaded in to a ‘V’ blender.Starch, xanthan gum, talc, banana flavor, silicon dioxide, sugar, coatedmethylphenidate-ion Exchange Resin complex-matrix prepared as describedin Part C, and Uncoated Methylphenidate-Ion Exchange Resin Complexprepared as described in Part A of this Example, were loaded into the‘V’ blender and mixed for 10 minutes. The resulting blend contained 80parts by weight of sustained release MPH (coated matrix) to 20 parts byweight immediate release MPH (uncoated complex), based on the totalweight of MPH in the final ER powder blend formulation. TheMethylphenidate ER Powder blend was filled into an appropriate containerwhich, when reconstituted with purified water, achieved a concentrationequivalent to 25 mg methylphenidate hydrochloride per 5 mL.

Example 5 Methylphenidate ER Powder for Aqueous Oral Suspension

In this example, the MPH ER powder is a combination of (i) an uncoatedmethylphenidate-ion exchange resin, (ii) a coated (Eudragit RS/RLpolyacrylate based coat, 30% weight gain) methylphenidate-ion exchangeresin complex-hydrophilic polymer matrix, and (iii) diluent granules.

A. Uncoated Methylphenidate-Ion Exchange Resin Complex

Ingredients Quantity Methylphenidate HCl 3100 g Amberlite ® IRP69 7693 gSodium Polystyrene Sulfonate Resin Purified Water* Qs* *Removed duringprocessing

The methylphenidate-ion exchange resin complex was prepared by firstadding 80 L of purified water into the vessel and methylphenidate HClwas dissolved therein by continuous mixing. Amberlite® IRP69 ionexchange resin was dispersed in the solution with continuous mixing,which mixing was continued for 60 minutes. Water was removed byfiltration process followed by rinsing twice using purified water (40L). Wet methylphenidate-ion exchange resin complex was then dried untilthe moisture content was 3% to 7%. Dried methylphenidate-ion exchangeresin complex was passed through a CO-MIL device fitted with a standard40 mesh screen. This was the uncoated methylphenidate-ion exchange resincomplex.

B. Precoated Methylphenidate-Ion Exchange Resin Complex-Matrix

Ingredients Quantity Uncoated Methylphenidate - Ion Exchange 8500 gResin Complex (from Part A) Kollidon ® K30 657 g Purified water* 2629 gPurified Water* Qs* *Removed during processing

In a separate container the PVP was dissolved in 2629 g of purifiedwater (Povidone solution). Uncoated Methylphenidate-ion exchange resincomplex prepared as described in A was mixed with the povidone solutionuntil a polymer weight gain of 7.73% was achieved, with continuousmixing to form a uniform mass of precoated methylphenidate-ion exchangeresin-PVP matrix. Wet mass was dried until the moisture content was 15%to 25%. Semi-dried material was then passed through a CO-MIL devicefitted with a standard 40 mesh screen. Milled methylphenidate-ionexchange resin matrix was further dried until moisture content was 3% to7%. Dried methylphenidate-ion exchange resin matrix was passed through aCO-MIL device fitted with a standard 40 mesh screen. This was theprecoated methylphenidate-ion exchange resin complex-matrix.

C. Coated Methylphenidate Ion Exchange Resin Complex-Matrix

Ingredient Quantity Precoated Methylphenidate - Ion Exchange 600 g ResinComplex - Matrix (From Part B) Eudragit ™ RS ** 376.30 g Eudragit ™ RL** 75.26 g Triethyl citrate 27 g Talc 33.87 g Purified Water* 694.56 g*Removed during processing ** (30% w/w aqueous dispersion)

The precoated methylphenidate-ion exchange resin complex matrix wascoated as follows. The coating solution was prepared by dispersingtriethyl citrate and talc in purified water using a high shear mixer(Talc dispersion). In a separate container Eudragit™ dispersion wasprepared by mixing Eudragit™ RS 30D [a pH-independent, 30% aqueousdispersion of poly (ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1)]and Eudragit™ RL 30D [a 30% aqueous dispersion, pH independent polymer,poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethylmethacrylate chloride) 1:2:0.2)]. The Talc dispersion was mixed with theEudragit™ RS/RL dispersion. The coating process was performed in a fluidbed processor equipped with Wurster column by applying coating solutiononto the precoated methylphenidate-ion exchange resin complex-matrixfrom Part B until in 30% weight gain was achieved. The coatedmethylphenidate-ion exchange resin complex-matrix was passed throughSieve No. 40 mesh screen after coating. No curing at elevatedtemperature was performed.

D. Diluent Granules

Ingredient Quantity Poloxamer ™ 188 30 g Purified water* 600 g Sugar8260.63 g Sodium citrate 231.76 g Anhydrous citric acid 309.6 g Sodiumbenzoate 120 g Sucralose 48 g *Removed during processing

In a separate container, poloxamer surfactant was dissolved in purifiedwater (poloxamer solution). Sugar, sodium citrate, anhydrous citricacid, sodium benzoate, and sucralose were added into high sheargranulator and granulation process was performed using poloxamersolution. Wet granules were dried using fluid bed drier until moisturelevel was below 1.50%. Dried granules were then milled through Fitz millequipped with 20 mesh screen. This was the Diluent Granules.

E. Methylphenidate ER Powder Blend

Ingredient Quantity Diluent Granules (Part D) 480 g Starch 44.16 gXanthan gum 4.8 g Talc 6.4 g Banana flavor 4.8 g Silicon dioxide 6.4 gSugar 16.44 g Coated Methylphenidate - Ion 65.72 g exchange resincomplex - matrix Uncoated Methylphenidate - Ion 11.23 g exchange resincomplex

Diluent granules prepared as in Part D were loaded in to a ‘V’ blender.Starch, xanthan gum, talc, banana flavor, silicon dioxide, sugar, coatedmethylphenidate-ion exchange resin complex matrix prepared as in Part C,and Uncoated Methylphenidate ion exchange resin complex prepared asdescribed in Part A were loaded into the ‘V’ blender and mixed for 10minutes. The resulting methylphenidate ER powder blend contained a ratioof 80 parts by weight MPH in sustained release form (coatedmethylphenidate ion exchange resin complex matrix) to 20 parts by weightMPH in immediate release form (uncoated MPH ion exchange resin complex),based on the total weight of MPH in the MPH ER powder blend.

The Methylphenidate ER Powder blend was filled into an appropriatecontainer which, when reconstituted with purified water, achieved aconcentration equivalent to 25 mg methylphenidate hydrochloride per 5mL.

Example 6 pH-Chemical Stability of Methylphenidate Extended ReleasePowder Blend in an Aqueous Oral Suspension, 25 mg/5 mL

Methylphenidate shows pH-dependent stability in aqueous media, and itsprimary degradant, threo-α-phenyl-2-piperidineacetic acid, is primarilygenerated through hydrolysis. A pH stability study was conducted onsuspensions based on the reconstituted methylphenidate ER powder blendprepared as described in Example 1 [methylphenidate-ion exchange resincomplex prepared as described in Example 1, Part A (weight ratio ofapproximately 80 parts by weight coated to approximately 20% parts byweight uncoated methylphenidate-ion exchange resin complex in Example 1,based on the weight ratio of the methylphenidate in each component) wereloaded into a ‘V’ blender and mixed for 10 minutes. The methylphenidateER powder blend for suspension was added with purified water to yield asuspension containing methylphenidate equivalent to 25 mg per 5 mLmethylphenidate hydrochloride.

The aqueous suspension containing the methylphenidate extended releasepowder blend of Example 1 was adjusted with either HCl or NaOH to obtainvarious samples with different pHs ranging from 2 to 6. The samples wereplaced at 40° C./75% RH (relative humidity) for 1 month and tested fortheir potency and impurity. The stability of the suspension was assessedbased on the percent (%) potency remaining when compared to the initialpotency of the suspension and its primary degradant,threo-α-phenyl-2-piperidineacetic acid.

The results are provided in the following table and FIG. 2.

% Potency pH @ 1 month % Impurity* 2.1 44.5 57.2 3.0 89.1 15.0 3.5 98.45.6 4.1 96.5 2.7 4.5 101.2 2.9 4.9 95.9 6.2 5.3 88.9 15.1 5.7 66.5 33.45.9 46.6 43.1 *impurity: Threo-α-Phenyl-2-piperidineacetic Acid

These results show the product is most stable at pH between 3.5 and 5.0,and becomes less stable when pH is above 5.0 or below 3.5. It is notedthat there is no direct correlation between the percentage of theimpurity and loss of potency.

Example 7 Single Dose Pharmacokinetics of an Extended ReleaseMethylphenidate Suspension

To determine the single-dose pharmacokinetics of an aqueous suspensionformulation, the MPH ER powder blend of Example 1 was combined withwater to achieve a concentration of about 25 mg/5 mL and the resultingsuspension was dosed at an amount equivalent to 60 mg racemicmethylphenidate HCl. This suspension was compared with two doses of acommercially available 30 mg immediate release liquid MPH (Methylin®,reference immediate release (IR) MPH), which was dosed at hours 0 and 6in adults.

The following results show that a single dose of a 60 mg aqueoussuspension formulation of the invention is bioequivalent to two 30-mgdoses of reference IR MPH, and the 60 mg aqueous suspension formulationof the invention has a lower peak plasma concentration than thereference IR MPH product.

30 healthy subjects aged 18 to 68 years (25 men, 5 women, mean 36.5years) were enrolled in this open-label, crossover study and randomlyassigned to receive the 60 mg methylphenidate aqueous suspensionformulation of the invention or the reference IR MPH after an overnightfast. Blood samples were collected prior to dose at hour 0 and atpost-dose hours 0.5, 1, 1.33, 1.67, 2, 2.5, 3, 4, 5, 6, 6.5, 7, 7.33,7.67, 8, 9.5, 9, 10, 12, 14, 16, 24 and 36. Plasma concentrations of d-and l-MPH were determined and pharmacokinetic parameters werecalculated. Twenty-eight subjects completed the study.

A. Pharmacokinetics

The pharmacokinetic profile is provided in FIG. 3. Followingadministration of the 60 mg aqueous oral suspension formulation of theinvention, the mean plasma d-MPH concentration increased rapidly forabout 1 hour and then continued to a slower increase until peaking at 5hours, after which a gradual decline in plasma concentration wasobserved. See FIG. 3.

Summary of d-Methylphenidate Mean Pharmacokinetic Parameters 60 mg TestIR MPH Reference Parameters (n = 28) (n = 28) AUC_(0-∞) 143.65 (50.67)151.31 (54.84) C_(max) (ng/mL) 13.61 (42.56) 20.94 (61.89) T_(max) (hr)5.00 (1.67-6.00) 7.33 (6.5-8.00) T_(1/2) (hr) 5.65 (15.01) 3.74 (16.29)T_(1/2) - Terminal phase elimination half life T_(max) - Time to peak(maximum) observed plasma drug concentration C_(max) - Peak (maximum)observed plasma drug concentration AUC_(0-α) - Area under theconcentration - time curve from time zero to infinity

The results for AUC_(0-α), C_(max) and T_(1/2) are presented asgeometric mean (percent coefficient of variation) and results forT_(max) presented as median (range).

The AUC_(0-∞) of d-MPH for the aqueous suspension of the invention andreference IR MPH were 143.65 and 153.31 ng-hr/mL, respectively.

B. Absorption

Following a single, 60 mg oral dose of the MPH extended releasesuspension prepared as in Example 1, in 28 healthy adult subjects underfasting conditions, d-methylphenidate mean (+SD) peak plasmaconcentrations (C_(max)) of 13.6 (±5.8) ng/mL occurred at a median timeof 5.0 hours after dosing. The C_(max) (ng/mL) was 20.94 for thereference IR MPH product. The results are illustrated in FIG. 4.

C. Metabolism and Excretion

Following a single 60 mg oral dose of the MPH extended release liquidsuspension prepared as in Example 1 in 28 healthy adult subjects underfasting conditions, the mean plasma terminal elimination half-life ofd-methylphenidate was 5.6 (+0.8) hours and T_(max) was 5 hours. For thereference IR MPH, the half-life was 3.74 hours and T_(max) was 7.33hours.

In humans, methylphenidate is metabolized primarily via deesterificationto alpha-phenyl-piperidine acetic acid (PPAA). The metabolite has littleor no pharmacologic activity.

After oral dosing of radiolabeled methylphenidate in humans, about 90%of the radioactivity was recovered in urine. The main urinary metabolitewas PPAA, accounting for approximately 80% of the dose.

D. Food Effects

In a study in adult volunteers to investigate the effects of a high-fatmeal on the bioavailability of the methylphenidate at a dose of 60 mg,the presence of food reduced the time to peak concentration byapproximately 1 hour (5 hours, fasted and 4 hours, fed). Overall, ahigh-fat meal increased the average C_(max) of the methylphenidate ERliquid suspension of the invention by about 28% and the AUC by about19%.

Example 8 Clinical Studies

The efficacy of the methylphenidate ER liquid suspension productprepared as described in Example 1 was evaluated in a randomized,double-blind, placebo-controlled, crossover, multicenter, laboratoryclassroom study conducted in 45 pediatric patients (ages 6 to 12 years)with ADHD. There was an open-label dose optimization period (4 to 6weeks) with an initial 20 mg dose of MPH ER liquid suspension once dailyin the morning. The dose could be titrated weekly in increments of 10 or20 mg until an optimal dose or maximum dose of 60 mg/day was reached.Subjects then entered a 2-week randomized, double-blind, crossovertreatment of the individually optimized dose of the tested MPH ERsuspension or placebo. At the end of each week, schoolteachers andraters evaluated the attention and behavior of the subjects in alaboratory classroom using the Swanson, Kotin, Agler, M-Flynn, andPelham (SKAMP) rating scale. Results of the study are summarized in FIG.5. SKAMP scores were statistically significantly lower (improved) duringtreatment with the MPH ER suspension of the invention as compared toplacebo. The onset of efficacy was determined to be 0.75 hours post-doseand efficacy was maintained throughout the entire 12-hour period.

All patents, patent publications, and other publications listed in thisspecification, are incorporated herein by reference. Furtherincorporated by reference are priority documents U.S. patent applicationSer. No. 14/657,151, filed Mar. 13, 2015, U.S. patent application Ser.No. 14/554,123, filed Nov. 26, 2014, now U.S. Pat. No. 9,040,083; U.S.patent application Ser. No. 14/299,421, filed Jun. 9, 2014, now U.S.Pat. No. 8,956,649; U.S. patent application Ser. No. 14/016,384, filedSep. 3, 2013, now U.S. Pat. No. 8,778,390; U.S. patent application Ser.No. 13/905,808, filed May 30, 2013, now U.S. Pat. No. 8,563,033; U.S.patent application Ser. No. 13/611,183, filed Sep. 12, 2012, now U.S.Pat. No. 8,465,765; U.S. patent application Ser. No. 13/244,706, filedSep. 26, 2011, now U.S. Pat. No. 8,287,903, and International PatentApplication No. PCT/US2011/024873, filed Feb. 15, 2011. While theinvention has been described with reference to a particularly preferredembodiment, it will be appreciated that modifications can be madewithout departing from the spirit of the invention. Such modificationsare intended to fall within the scope of the appended claims.

What is claimed is:
 1. A methylphenidate aqueous oral suspension,wherein said suspension has a pH of about 4.2; (i) an immediate releasemethylphenidate component; (ii) a sustained release methylphenidatecomponent comprising a water-insoluble, water-permeable, sustainedrelease barrier coated methylphenidate-ion exchange resincomplex-optional matrix, and (iii) water; wherein the aqueous oralsuspension provides a pharmacokinetic profile in which d-methylphenidatehas an area under the curve (AUC)_(0-∞) of about 114 ng-hr/mL to about180 ng-hr/mL following a single oral administration of the aqueous oralsuspension to adult subjects under fasted conditions at a doseequivalent to 60 mg racemic methylphenidate HCl.
 2. The methylphenidateaqueous oral suspension according to claim 1, wherein said suspensioncomprises at least about 80% w/w water based on the total weight of thesuspension.
 3. The methylphenidate aqueous oral suspension according toclaim 1, wherein the immediate release methylphenidate component and thesustained release methylphenidate component in said suspension providesa dose equivalent to about 25 mg racemic methylphenidate HCl per 5 mLsuspension.
 4. The methylphenidate aqueous oral suspension according toclaim 1, wherein the therapeutic effect of the suspension is observedand has an onset at least as early as 45-minutes and throughout anextended release profile in the subject following a single oraladministration.
 5. The methylphenidate aqueous oral suspension accordingto claim 1, wherein the barrier coated methylphenidate-ion exchangeresin complex of the sustained release component-optional matrixcomprises a matrix forming component, wherein said coating is over themethylphenidate-ion exchange resin complex-matrix.
 6. Themethylphenidate aqueous oral suspension according to claim 5, whereinthe methylphenidate-ion exchange resin complex-matrix comprises ahydrophilic polymer or co-polymer matrix forming component.
 7. Themethylphenidate aqueous oral suspension according to claim 6, whereinthe methylphenidate-ion exchange resin complex-matrix comprises ahydrophilic polymer in an amount of about 5 to about 20% by weight,based on the weight of the methylphenidate-ion exchange resincomplex-matrix.
 8. The methylphenidate aqueous oral suspension accordingto claim 1, wherein the methylphenidate in the immediate releasemethylphenidate component comprises about 20% w/w of the totalmethylphenidate in said suspension.
 9. The methylphenidate aqueous oralsuspension according to claim 1, wherein the immediate releasemethylphenidate component comprises an uncoated methylphenidate-ionexchange resin complex.
 10. The methylphenidate aqueous oral suspensionaccording to claim 1, wherein the immediate release methylphenidatecomponent comprises a methylphenidate-ion exchange resin complex havinga coating that provides immediate release.
 11. The methylphenidateaqueous oral suspension according to claim 1, wherein in thewater-insoluble, water-permeable, sustained release barrier coatedmethylphenidate-ion exchange resin complex of the sustained releasecomponent, the barrier coat is pH-independent and comprises a polyvinylacetate polymer and a plasticizer.
 12. The methylphenidate aqueous oralsuspension according to claim 1, wherein in the barrier coating of thewater-insoluble, water-permeable, sustained release barrier coatedmethylphenidate-ion exchange resin complex of the sustained releasecomponent, the barrier coat is pH-independent and comprisesethylcellulose.
 13. The methylphenidate aqueous oral suspensionaccording to claim 1, wherein in the water-insoluble, water-permeable,sustained release barrier coated methylphenidate-ion exchange resincomplex of the sustained release component, the barrier coat ispH-independent and comprises a methyl methacrylate polymer orco-polymer.
 14. The methylphenidate aqueous oral suspension according toclaim 1 wherein the suspension further comprises a buffering agentselected from the group consisting of one or more of a pharmaceuticallyacceptable acid consisting of citric acid, ascorbic acid, acetic acid,tartartic acid, phosphoric acid, a pharmaceutically acceptable salt ofcitric acid, ascorbic acid, acetic acid, tartartic acid, phosphoricacid, and mixtures thereof.
 15. A method of treating a patient having adisorder selected from Attention Deficit Disorder (ADD), AttentionDeficit Hyperactivity Disorder (ADHD), postural orthostatic tachycardiasyndrome, and narcolepsy, said method comprising delivering an effectiveamount of a methylphenidate aqueous oral suspension according to claim 1to the patient.
 16. The method according to claim 15, wherein theimmediate release methylphenidate component and the sustained releasemethylphenidate component in the suspension provides a methylphenidatedose equivalent to about 25 mg racemic methylphenidate HCl per 5 mL. 17.The method according to claim 15, wherein the suspension has an onset ofaction for methylphenidate of about 45 minutes and a continuous extendedrelease profile of up to about 12 hours post-dosing.
 18. Amethylphenidate aqueous oral suspension, wherein said methylphenidateaqueous oral suspension has a pH of about 4.2, (i) an immediate releasemethylphenidate component, (ii) a sustained release methylphenidatecomponent comprising a water-insoluble, water-permeable, pH-independentsustained release barrier coated methylphenidate-ion exchange resincomplex, and (iii) water, wherein said methylphenidate aqueous oralsuspension provides a pharmacokinetic profile in which d-methylphenidatehas an area under the curve (AUC)_(0-∞) of 114 ng-hr/mL to 180 ng-hr/mLin adult subjects following a single oral dose of said methylphenidateaqueous oral suspension under fasted conditions and a reduced T_(max) inadults fed with a high-fat meal prior to administration compared toadult subjects in a fasted state prior to said single oral dose, andwherein following a single oral dose said methylphenidate aqueous oralsuspension at a dose equivalent to 60 mg racemic methylphenidate HCl hasa therapeutic effect which has an onset at least as early as 45-minutesand which is maintained for at least about 12 hours post-dosing.